Polatuzumab vedotin acMMAE + MMAE integrated population PK model (Lu 2019)
Source:vignettes/articles/Lu_2019_polatuzumab.Rmd
Lu_2019_polatuzumab.Rmd
library(nlmixr2lib)
library(PKNCA)
#>
#> Attaching package: 'PKNCA'
#> The following object is masked from 'package:stats':
#>
#> filter
library(rxode2)
#> rxode2 5.0.2 using 2 threads (see ?getRxThreads)
#> no cache: create with `rxCreateCache()`
library(dplyr)
#>
#> Attaching package: 'dplyr'
#> The following objects are masked from 'package:stats':
#>
#> filter, lag
#> The following objects are masked from 'package:base':
#>
#> intersect, setdiff, setequal, union
library(tidyr)
library(ggplot2)Model and source
- Citation: Lu D, Lu T, Gibiansky L, Li X, Li C, Agarwal P, Shemesh CS, Shi R, Dere RC, Hirata J, Miles D, Chanu P, Girish S, Jin JY. Integrated Two-Analyte Population Pharmacokinetic Model of Polatuzumab Vedotin in Patients With Non-Hodgkin Lymphoma. CPT Pharmacometrics Syst Pharmacol. 2020;9(1):48-59.
- Article: https://doi.org/10.1002/psp4.12482 (PMID 31749251)
- Supplement: NONMEM control stream + equations (open access; published alongside the article).
The model couples two submodels (paper Figure 1):
-
acMMAE submodel – antibody-conjugated MMAE, two-compartment, with three parallel elimination pathways from the central compartment:
-
CL_NS(nonspecific linear clearance) declining slowly with time on repeated dosing via a sigmoidal Hill functionCL_NS(t) = CL_INF * (1 + CL_INF,EMAX * T50^gamma / (T50^gamma + t^gamma)), -
CL_t(rapidly-declining linear clearance)CL_t(t) = CL_T0 * exp(-kdes * t), and -
CL_MM(Michaelis-Menten clearance)CL_MM = Vmax * V1 / (KM + A1/V1).
-
-
MMAE submodel – unconjugated MMAE, two-compartment, with apparent parameters (true fraction of formation cannot be estimated, so
CL_MMAEandV_MMAEabsorb the formation-fraction scalar). The central MMAE compartment is driven by the three acMMAE elimination pathways with relative conversion fractions modulated by a time-decaying multiplier on FRAC_NS (Lu 2019 Eq. 2):KINPUT = FRAC_NS * (CL_NS + FRAC_CLT * CL_t + FRAC_MM * CL_MM) / V1 FRAC_NS(t) = FRAC_0 * (1 + FRAC_T * exp(-alpha * t))plus parallel linear (
CL_MMAE) and Michaelis-Menten (Vmax_MMAE / KSS) elimination from the MMAE central compartment.
Modeling is in MMAE-equivalent micrograms (a pola dose of 1.8 mg/kg
in an 80 kg patient corresponds to
1.8 mg/kg * 80 kg * 1000 ug/mg * 3.65 * 718 / 145001 = 2603 ug
of acMMAE into the central acMMAE compartment, where 3.65 is the mean
drug-to-antibody ratio, 718 g/mol is the MMAE molecular weight, and
145001 g/mol is the antibody-drug conjugate molecular weight; Methods
section).
Population
The integrated final model was fit to pooled data from four clinical studies (Lu 2019 Table S1) in 460 adult patients with non-Hodgkin lymphoma (NHL):
- DCS4968g (NCT01290549, Phase I/Ib) – 95 patients with relapsed/ refractory (R/R) B-cell NHL or chronic lymphocytic leukaemia, single-agent pola at 0.1, 0.25, 0.5, 1.0, 1.8, or 2.4 mg/kg q3w; or pola 2.4 mg/kg q3w + rituximab. Used the most-intensive PK sampling and contributed >30 plasma samples / patient.
- GO27834 / ROMULUS (NCT01691898, Phase Ib/II) – 142 R/R B-cell NHL (DLBCL or FL) patients on pola 1.8 or 2.4 mg/kg q3w + rituximab or obinutuzumab.
- GO29365 (NCT02257567, Phase Ib/II) – 106 R/R FL or DLBCL patients on pola 1.8 mg/kg q3w (DLBCL) or q4w (FL) + bendamustine + rituximab or obinutuzumab.
- GO29044 (NCT01992653, Phase Ib/II) – 45 previously untreated DLBCL patients on pola 1.0-2.4 mg/kg q3w + rituximab or obinutuzumab + cyclophosphamide + doxorubicin.
The pooled dataset contributed 4,215 acMMAE and 4,194 unconjugated MMAE concentration-time pairs after exclusions (post-first-dose BLQ values: 4.5% of acMMAE and 9.2% of MMAE; observations more than 1,008 hours = 6 weeks since the most recent dose were excluded as not clinically relevant). Sensitivity analyses were performed at body weight 5th-95th percentiles of 48.7 to 118 kg (Lu 2019 Figure 3 annotation).
The reference subject for the model’s typical-value parameters is a 75 kg male, R/R, non-Asian, ECOG >= 1, single-agent (no rituximab/obinutuzumab), normal hepatic function, with serum albumin 35 g/L, baseline B-cell count of 1 cell/uL, and SPD tumor burden of 5,000 mm^2.
mod_meta <- rxode2::rxode(readModelDb("Lu_2019_polatuzumab"))
#> ℹ parameter labels from comments will be replaced by 'label()'
str(mod_meta$meta$population, max.level = 1)
#> List of 13
#> $ n_subjects : int 460
#> $ n_studies : int 4
#> $ n_observations : chr "4215 acMMAE + 4194 unconjugated MMAE concentration-time pairs (Lu 2019 Results section first paragraph)"
#> $ age_range : chr "Adults with NHL (Lu 2019 does not tabulate age in the main paper; the four constituent studies enrolled adult p"| __truncated__
#> $ weight_range : chr "5th-95th percentile 48.7-118 kg per Lu 2019 Figure 3 sensitivity-analysis annotation; reference 75 kg used for "| __truncated__
#> $ sex_female_pct : num NA
#> $ race_ethnicity : chr "Tested as Asian vs non-Asian indicator only in the final model (RACE_ASIAN); a multiplicative effect on V1 (e_a"| __truncated__
#> $ disease_state : chr "Relapsed/refractory or previously untreated B-cell non-Hodgkin lymphoma (NHL): diffuse large B-cell lymphoma (D"| __truncated__
#> $ dose_range : chr "Pola 0.1-2.4 mg/kg IV every 3 weeks (Q3W) as monotherapy or in combination with rituximab, obinutuzumab, bendam"| __truncated__
#> $ regions : chr "Multi-regional (the four constituent studies were global Phase I/Ib/II trials NCT01290549, NCT01691898, NCT0225"| __truncated__
#> $ studies : chr "DCS4968g (NCT01290549, Phase I/Ib single-agent and Pola+R run-in), GO27834 / ROMULUS (NCT01691898, Phase Ib/II "| __truncated__
#> $ reference_subject: chr "75 kg, ALB 35 g/L, TUMSZ 5000 mm^2 SPD, B-cell 1 cell/uL (so max(1, BLBCELL) = 1), male, R/R, non-Asian, normal"| __truncated__
#> $ notes : chr "Population characteristics drawn from Lu 2019 main text Results, Figure 3 sensitivity-analysis annotations, and"| __truncated__Source trace
Every ini() entry in
inst/modeldb/specificDrugs/Lu_2019_polatuzumab.R carries an
in-file comment pointing to Lu 2019 Table 1, Table 2, or Table S3. The
table below collates them.
| Parameter (nlmixr2lib) | Source quantity | Value | Source location |
|---|---|---|---|
lkdes |
kdes | 0.0046 1/hour | Table 1, theta1 |
lclt0 |
CL_T (initial) | 0.00623 L/hour | Table 1, theta2 |
lclinf |
CL_INF | 0.0344 L/hour | Table 1, theta3 |
lvc |
V1 | 3.15 L | Table 1, theta4 |
lvp |
V2 | 3.98 L | Table 1, theta5 |
lq |
Q | 0.0145 L/hour | Table 1, theta6 |
lvmax_ac |
Vmax (acMMAE) | 0.0203 ng/mL/hr | Table 1, theta7 |
lkm_ac |
KM (acMMAE) | 0.604 ng/mL | Table 1, theta8 |
clinf_emax |
CL_INF,EMAX | 0.223 | Table 1, theta9 |
lt50_mo |
T50 (months) | 3.53 months | Table 1, theta10 |
gamma_ns |
gamma | 2.27 | Table 1, theta11 |
lvc_mmae |
V_MMAE (apparent) | 82.2 L | Table 1, theta12 |
lcl_mmae |
CL_MMAE (apparent) | 1.89 L/hour | Table 1, theta13 |
lq_mmae |
Q_MMAE (apparent) | 36.3 L/hour | Table 1, theta14 |
lvp_mmae |
V2_MMAE (apparent) | 200 L | Table 1, theta15 |
lvmax_mmae |
Vmax (MMAE) | 0.0307 ng/mL/hr | Table 1, theta16 |
lkss_mmae |
KSS (MMAE) | 0.581 ng/mL | Table 1, theta17 |
lfrac_clt |
FRAC_CLT | 3.70 | Table 1, theta18 |
lfrac_mm |
FRAC_MM | 2.72 | Table 1, theta19 |
lalph_mo |
alpha (1/month) | 0.167 1/month | Table 1, theta20 |
frac_t |
FRAC_T | 0.139 | Table 1, theta21 |
e_wt_clinf |
WT on CL_INF | 0.73 | Table 2, theta22 |
e_wt_v |
WT on V1, V2, Q (shared) | 0.50 | Table 2, theta23 |
e_sexf_v1 |
sex on V1 (1/1.20) | 0.8333 | Table 2, theta24 (inverted) |
e_asian_v1 |
Asian on V1 | 0.929 | Table 2, theta25 |
e_line1l_v1 |
Treatment-naive on V1 | 1.20 | Table 2, theta26 |
e_sexf_clinf |
sex on CL_INF (1/1.10) | 0.9091 | Table 2, theta27 (inverted) |
e_alb_clinf |
ALB on CL_INF (power) | -0.247 | Table 2, theta28 |
e_combo_rg_clinf |
R/G combo on CL_INF | 0.844 | Table 2, theta29 |
e_blbcell_clinf |
B-cell on CL_INF (power) | 0.0212 | Table 2, theta30 |
e_tumsz_clinf |
TUMSZ on CL_INF (linear) | 0.0521 | Table 2, theta31 |
e_line1l_kdes |
Treatment-naive on kdes | 3.38 | Table 2, theta32 |
e_combo_rg_kdes |
R/G combo on kdes | 0.932 | Table 2, theta33 |
e_line1l_clt |
Treatment-naive on CL_T | 3.53 | Table 2, theta34 |
tmbd50_clt |
TUMSZ50 on CL_T | 1150 mm^2 | Table 2, theta35 |
bcell_thr_clt |
B-cell threshold on CL_T | 121 cells/uL | Table 2, theta36 |
e_blbcell_clt |
B-cell power on CL_T | 0.578 | Table 2, theta37 |
e_wt_frac |
WT on FRAC_NS (power) | -0.467 | Table 2, theta38 |
e_sexf_frac |
sex on FRAC_NS (1/0.911) | 1.0977 | Table 2, theta39 (inverted) |
e_line1l_frac |
Treatment-naive on FRAC_NS | 0.756 | Table 2, theta40 |
e_combo_rg_frac |
R/G combo on FRAC_NS | 0.709 | Table 2, theta41 |
e_hepimp_frac |
NCI ODWG hep. impairment on FRAC_NS | 1.19 | Table 2, theta42 |
e_ecog_ge1_frac |
ECOG_GE1 on FRAC_NS (1/0.905) | 1.1050 | Table 2, theta43 (inverted) |
e_alb_frac |
ALB on FRAC_NS (power) | -0.613 | Table 2, theta44 |
CcpropSd |
sqrt(sigma1^2) | 0.1594 | Table S3, Sigma11 = 0.0254 |
CmmaepropSd |
sqrt(sigma2^2) | 0.2694 | Table S3, Sigma22 = 0.0726 |
| ODE system (4 states) | Lu 2019 Eq. 1 + supplement | Supplement $DES + Equations |
Inter-individual variability (omega^2 stored as variances on the log-normal scale; %CV = 100 * sqrt(exp(omega^2) - 1)):
| Parameter | omega^2 (Table S3) | %CV |
|---|---|---|
| CL_T | 1.89 | 138 |
| CL_INF | 0.0376 | 19.5 |
| V1 | 0.0151 | 12.3 |
| V2 | 0.107 | 32.7 |
| Q | 0.0538 | 23.2 |
| Vmax (ac) | 0.462 | 67.9 |
| FRAC_NS | 0.0972 | 31.2 |
| CL_MMAE | 0.115 | 33.9 |
| V2_MMAE | 0.0422 | 20.5 |
Errata
The supplement’s printed Equations section contains a sign typo on the acMMAE peripheral compartment ODE:
Supplement Equations (as printed):
dA2/dt = -K12 A1 - K21 A2
This is internally inconsistent with mass balance and with the supplement’s own NONMEM control stream, which gives:
DADT(2) = -K21*A(2) + K12*A(1)i.e., dA2/dt = +K12 A1 - K21 A2. The packaged model
adopts the NONMEM-control-stream form (the +K12 sign), which conserves
total acMMAE mass under the linear distribution flux. The published
Figure 2(a) total-clearance curve and the cycle 1 / cycle 6 exposure
values in Table 3 are derivable only with this sign convention.
Virtual cohort
We simulate a 200-subject virtual cohort approximating the Lu 2019 study population:
set.seed(20260426L)
n_subj <- 200L
n_cycles <- 6L
cycle_hr <- 504 # 21-day cycle in hours
# Body weight: log-normal anchored at the published reference 75 kg, with
# spread chosen to reproduce the Figure 3 sensitivity-analysis 5th-95th
# percentile range of 48.7-118 kg.
wt <- exp(rnorm(n_subj, mean = log(75), sd = 0.20))
wt <- pmin(pmax(wt, 48.7), 118)
# Demographics distributions: sex 50/50; treatment-naive 10% (most studies
# enroll R/R patients with one Phase Ib/II first-line cohort, GO29044, n=45);
# Asian race 15% (representative of the multi-regional pool); albumin
# centered on 38 g/L with SD 4 (NHL clinical norm); ECOG_GE1 50/50 (a typical
# split in NHL studies); hepatic impairment 5% (rare in B-cell NHL trials);
# combo R/G 60% (most patients receive an anti-CD20 partner across the four
# studies); B-cell counts log-normally distributed centered at the threshold
# 121 cells/uL; tumor SPD log-normal centered on the 5,000 mm^2 reference.
sexf <- rbinom(n_subj, 1, 0.50)
naive <- rbinom(n_subj, 1, 0.10)
asian <- rbinom(n_subj, 1, 0.15)
combo <- rbinom(n_subj, 1, 0.60)
hepimp <- rbinom(n_subj, 1, 0.05)
ecog1 <- rbinom(n_subj, 1, 0.50)
alb <- pmin(pmax(rnorm(n_subj, 38, 4), 25), 50)
bcell <- pmin(pmax(exp(rnorm(n_subj, log(50), 1.2)), 0.5), 800)
tumsz <- pmin(pmax(exp(rnorm(n_subj, log(5000), 0.7)), 200), 25000)
# MMAE-equivalent dose factor: pola_ug/kg * WT_kg * 3.65 * 718 / 145001
mmae_dose_factor <- 3.65 * 718 / 145001
make_subject <- function(id, wt_kg, sexf_ind, naive_ind, asian_ind,
combo_ind, hepimp_ind, ecog1_ind,
alb_val, bcell_val, tumsz_val) {
pola_dose_ug <- 1.8 * 1000 * wt_kg # 1.8 mg/kg in ug
mmae_eq_ug <- pola_dose_ug * mmae_dose_factor
ev <- rxode2::et() |>
rxode2::et(amt = mmae_eq_ug, cmt = "acmmae_central",
ii = cycle_hr, addl = n_cycles - 1L, time = 0) |>
rxode2::et(seq(0.5, n_cycles * cycle_hr, length.out = 100),
cmt = "Cc") |>
as.data.frame()
ev$id <- id
ev$WT <- wt_kg
ev$SEXF <- sexf_ind
ev$LINE_1L <- naive_ind
ev$RACE_ASIAN <- asian_ind
ev$COMBO_RG <- combo_ind
ev$HEPIMP <- hepimp_ind
ev$ECOG_GE1 <- ecog1_ind
ev$ALB <- alb_val
ev$BLBCELL <- bcell_val
ev$TUMSZ <- tumsz_val
ev$pola_dose_mg <- pola_dose_ug / 1000
ev$mmae_eq_ug <- mmae_eq_ug
ev
}
events <- do.call(rbind, lapply(seq_len(n_subj), function(i) {
make_subject(i, wt[i], sexf[i], naive[i], asian[i],
combo[i], hepimp[i], ecog1[i],
alb[i], bcell[i], tumsz[i])
}))
stopifnot(length(unique(events$id)) == n_subj)Typical-subject simulation (Figure 2 reproduction)
A single typical-subject curve replicates Lu 2019 Figure 2: a typical
patient receives 1.8 mg/kg q3w for 6 cycles (the labeled regimen). The
deterministic typical-value path uses rxode2::zeroRe().
mod <- rxode2::rxode(readModelDb("Lu_2019_polatuzumab"))
#> ℹ parameter labels from comments will be replaced by 'label()'
typ <- mod |> rxode2::zeroRe()
typ_events <- rxode2::et() |>
rxode2::et(amt = 1.8 * 1000 * 80 * mmae_dose_factor,
cmt = "acmmae_central",
ii = cycle_hr, addl = n_cycles - 1L, time = 0) |>
rxode2::et(seq(0.5, n_cycles * cycle_hr, length.out = 1500), cmt = "Cc")
# Lu 2019 Figure 2 caption: "typical patient ... bodyweight = 80 kg ... MMAE
# equivalent dose = 2,600 ug." We adopt the same WT = 80 kg reference subject.
typ_events$WT <- 80
typ_events$SEXF <- 0
typ_events$LINE_1L <- 0
typ_events$RACE_ASIAN <- 0
typ_events$COMBO_RG <- 0
typ_events$HEPIMP <- 0
typ_events$ECOG_GE1 <- 1
typ_events$ALB <- 35
typ_events$BLBCELL <- 1
typ_events$TUMSZ <- 5000
typ_sim <- rxode2::rxSolve(typ, typ_events, returnType = "data.frame")
#> ℹ omega/sigma items treated as zero: 'etalclt', 'etalclinf', 'etalvc', 'etalvp', 'etalq', 'etalvmax_ac', 'etalfrac_ns', 'etalcl_mmae', 'etalvp_mmae'
typ_sim |>
mutate(
cl_mm = vmax_ac / (km_ac + acmmae_central / v1), # CL_MM in L/hour
cl_total = cl_ns + cl_t + cl_mm
) |>
select(time, cl_ns, cl_t, cl_mm, cl_total) |>
pivot_longer(c(cl_ns, cl_t, cl_mm, cl_total),
names_to = "pathway", values_to = "cl_Lhr") |>
mutate(pathway = factor(pathway,
levels = c("cl_ns", "cl_t", "cl_mm", "cl_total"),
labels = c("CL_NS", "CL_t", "CL_MM", "Total CL"))) |>
ggplot(aes(time, cl_Lhr, colour = pathway)) +
geom_line(linewidth = 0.8) +
geom_vline(xintercept = seq(0, by = cycle_hr, length.out = n_cycles),
linetype = "dashed", alpha = 0.3) +
labs(x = "Time (hour)", y = "Clearance of acMMAE (L/hour)",
colour = NULL,
caption = "Replicates Lu 2019 Figure 2(a).")
Lu 2019 Figure 2(a) replication: time-dependent change of the three acMMAE clearance pathways and their total under repeated 1.8 mg/kg q3w dosing for 6 cycles in a typical 80 kg patient. CL_NS slowly declines via the Hill function; CL_t rapidly decays toward zero; CL_MM contributes negligibly at therapeutic doses (overlaps the x-axis). Black arrow positions mark the dosing times at 0, 504, 1008, 1512, 2016, and 2520 hours.
typ_sim |>
mutate(
cl_mm = vmax_ac / (km_ac + acmmae_central / v1),
input_clns_ugh = frac_ns * cl_ns * acmmae_central / v1,
input_clt_ugh = frac_ns * frac_clt * cl_t * acmmae_central / v1,
input_clmm_ugh = frac_ns * frac_mm * cl_mm * acmmae_central / v1,
input_total_ugh = input_clns_ugh + input_clt_ugh + input_clmm_ugh
) |>
select(time, input_clns_ugh, input_clt_ugh, input_clmm_ugh, input_total_ugh) |>
pivot_longer(c(input_clns_ugh, input_clt_ugh, input_clmm_ugh, input_total_ugh),
names_to = "pathway", values_to = "rate_ugh") |>
mutate(pathway = factor(pathway,
levels = c("input_clns_ugh", "input_clt_ugh",
"input_clmm_ugh", "input_total_ugh"),
labels = c("CL_NS input", "CL_t input",
"CL_MM input", "Total input"))) |>
ggplot(aes(time, rate_ugh, colour = pathway)) +
geom_line(linewidth = 0.8) +
geom_vline(xintercept = seq(0, by = cycle_hr, length.out = n_cycles),
linetype = "dashed", alpha = 0.3) +
labs(x = "Time (hour)", y = "Rate of input to MMAE central (ug/hour)",
colour = NULL,
caption = "Replicates Lu 2019 Figure 2(b).")
Lu 2019 Figure 2(b) replication: time-dependent input rate (ug/hour) to the unconjugated MMAE central compartment from each acMMAE elimination pathway under repeated 1.8 mg/kg q3w dosing for 6 cycles. The decline of the cumulative input rate per cycle is most pronounced from cycle 1 to cycle 2, driven by the CL_t pathway.
typ_sim |>
select(time, Cc, Cmmae) |>
pivot_longer(c(Cc, Cmmae), names_to = "analyte", values_to = "conc") |>
mutate(analyte = recode(analyte,
Cc = "acMMAE (ng/mL)",
Cmmae = "Unconjugated MMAE (ng/mL)")) |>
ggplot(aes(time, conc)) +
geom_line(colour = "steelblue", linewidth = 0.8) +
facet_wrap(~ analyte, ncol = 1, scales = "free_y") +
scale_y_log10() +
labs(x = "Time (hour)", y = "Concentration (ng/mL)")
Typical-subject acMMAE (top) and unconjugated MMAE (bottom) plasma concentration-time profiles under 1.8 mg/kg q3w for 6 cycles in an 80 kg patient. Cycle 6 acMMAE Cmax should approximate the published cycle 6 mean (721 ng/mL) and cycle 6 MMAE Cmax should approximate the published mean (~2.27 ng/mL); see PKNCA cross-check below.
Population (VPC-style) simulation
Full population simulation with all between-subject variability and
residual error preserved. Dropping zeroRe() enables both
etas and proportional residual error from the model file.
pop_sim <- rxode2::rxSolve(
mod, events,
keep = c("WT", "SEXF", "LINE_1L", "RACE_ASIAN", "COMBO_RG",
"HEPIMP", "ECOG_GE1", "ALB", "BLBCELL", "TUMSZ",
"pola_dose_mg", "mmae_eq_ug"),
returnType = "data.frame"
)
pop_sim |>
filter(!is.na(Cc)) |>
group_by(time) |>
summarise(
p05 = quantile(Cc, 0.05, na.rm = TRUE),
p50 = quantile(Cc, 0.50, na.rm = TRUE),
p95 = quantile(Cc, 0.95, na.rm = TRUE),
.groups = "drop"
) |>
ggplot(aes(time, p50)) +
geom_ribbon(aes(ymin = p05, ymax = p95), fill = "steelblue", alpha = 0.3) +
geom_line(colour = "steelblue4", linewidth = 0.8) +
scale_y_log10() +
labs(x = "Time (hour)", y = "acMMAE concentration (ng/mL)")
VPC-style 5th / 50th / 95th percentile envelope of simulated acMMAE concentrations across 200 virtual subjects on 1.8 mg/kg q3w for 6 cycles. Replicates the structural shape of Lu 2019 Figure S1 (acMMAE pcVPC).
pop_sim |>
filter(!is.na(Cmmae)) |>
group_by(time) |>
summarise(
p05 = quantile(Cmmae, 0.05, na.rm = TRUE),
p50 = quantile(Cmmae, 0.50, na.rm = TRUE),
p95 = quantile(Cmmae, 0.95, na.rm = TRUE),
.groups = "drop"
) |>
ggplot(aes(time, p50)) +
geom_ribbon(aes(ymin = p05, ymax = p95), fill = "tomato", alpha = 0.3) +
geom_line(colour = "tomato4", linewidth = 0.8) +
scale_y_log10() +
labs(x = "Time (hour)", y = "Unconjugated MMAE concentration (ng/mL)")
VPC-style 5th / 50th / 95th percentile envelope of simulated unconjugated MMAE concentrations across 200 virtual subjects on 1.8 mg/kg q3w for 6 cycles. Replicates the structural shape of Lu 2019 Figure S1 (MMAE pcVPC), including the cycle-over-cycle decline in MMAE Cmax driven by the time-decaying FRAC_NS multiplier.
PKNCA validation by cycle vs. Lu 2019 Table 3
Lu 2019 Table 3 reports per-cycle mean +/- SD (CV%) for AUC0-tau,
Cmax, and Ctrough at cycles 1, 3, and 6 (and a cycle-30 hypothetical
steady-state) under 1.8 mg/kg q3w. We compute matching NCA on the
simulated population using PKNCA, with each observation assigned to its
cycle interval [(c - 1) * 504, c * 504) hours.
add_cycle <- function(df) {
df |>
mutate(cycle_n = pmin(n_cycles,
pmax(1L,
as.integer(floor((time - 1e-9) / cycle_hr) + 1L))),
cycle = factor(cycle_n, levels = 1:n_cycles),
time_in_cycle = time - (cycle_n - 1) * cycle_hr)
}
acmmae_nca <- pop_sim |>
filter(!is.na(Cc), time > 0) |>
add_cycle() |>
filter(cycle_n %in% c(1, 3, 6)) |>
transmute(id, cycle, time = time_in_cycle, Cc)
mmae_nca <- pop_sim |>
filter(!is.na(Cmmae), time > 0) |>
add_cycle() |>
filter(cycle_n %in% c(1, 3, 6)) |>
transmute(id, cycle, time = time_in_cycle, Cmmae)
dose_df <- events |>
filter(evid == 1) |>
mutate(cycle_n = pmin(n_cycles,
pmax(1L, as.integer(round(time / cycle_hr) + 1L))),
cycle = factor(cycle_n, levels = 1:n_cycles),
time_in_cycle = 0,
amt = mmae_eq_ug) |>
filter(cycle_n %in% c(1, 3, 6)) |>
transmute(id, cycle, time = time_in_cycle, amt)
ac_conc <- PKNCA::PKNCAconc(acmmae_nca, Cc ~ time | cycle + id,
concu = "ng/mL", timeu = "hour")
ac_dose <- PKNCA::PKNCAdose(dose_df, amt ~ time | cycle + id,
doseu = "ug")
intervals_q3w <- data.frame(
start = 0,
end = cycle_hr,
cmax = TRUE,
tmax = TRUE,
auclast = TRUE,
ctrough = TRUE
)
ac_nca_res <- PKNCA::pk.nca(PKNCA::PKNCAdata(ac_conc, ac_dose,
intervals = intervals_q3w))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> ■■■■■■■■■■■■■■■■■■■■■■■■■ 79% | ETA: 1s
#> Warning: Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
ac_nca_long <- as.data.frame(ac_nca_res$result)
mmae_conc <- PKNCA::PKNCAconc(mmae_nca, Cmmae ~ time | cycle + id,
concu = "ng/mL", timeu = "hour")
mmae_dose <- PKNCA::PKNCAdose(dose_df, amt ~ time | cycle + id,
doseu = "ug")
mmae_nca_res <- PKNCA::pk.nca(PKNCA::PKNCAdata(mmae_conc, mmae_dose,
intervals = intervals_q3w))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> ■■■■■■■■■■■■■■ 42% | ETA: 3s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.333333) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (15.3535) is not allowed
mmae_nca_long <- as.data.frame(mmae_nca_res$result)acMMAE: simulated vs. published
# Reduce per-subject NCA results to mean +/- SD by cycle, in the same units
# as Lu 2019 Table 3: AUC in ng*day/mL (= AUC_ng_h_mL / 24), Cmax in ng/mL,
# Ctrough in ng/mL.
summarize_cycle <- function(df, conv = c(auclast = 1 / 24,
cmax = 1,
ctrough = 1)) {
df |>
filter(PPTESTCD %in% names(conv)) |>
mutate(value = PPORRES * conv[PPTESTCD]) |>
group_by(cycle, PPTESTCD) |>
summarise(mean = mean(value, na.rm = TRUE),
sd = sd(value, na.rm = TRUE),
.groups = "drop") |>
pivot_wider(names_from = PPTESTCD,
values_from = c(mean, sd))
}
ac_summary <- summarize_cycle(ac_nca_long)
ac_summary_pretty <- ac_summary |>
transmute(
Cycle = cycle,
`AUC (ng*day/mL) sim` = sprintf("%.0f +/- %.0f", mean_auclast, sd_auclast),
`Cmax (ng/mL) sim` = sprintf("%.0f +/- %.0f", mean_cmax, sd_cmax),
`Ctrough (ng/mL) sim` = sprintf("%.1f +/- %.1f", mean_ctrough, sd_ctrough)
)
published_ac <- tibble::tibble(
Cycle = factor(c(1, 3, 6), levels = 1:n_cycles),
`AUC (ng*day/mL) published` = c("2,020 +/- 571",
"2,640 +/- 522",
"2,900 +/- 577"),
`Cmax (ng/mL) published` = c("690 +/- 116",
"713 +/- 117",
"721 +/- 118"),
`Ctrough (ng/mL) published` = c("13.1 +/- 6.58",
"23.7 +/- 10.1",
"29.3 +/- 12.3")
)
knitr::kable(
dplyr::left_join(ac_summary_pretty, published_ac, by = "Cycle"),
caption = "acMMAE NCA -- simulated (200 virtual subjects, mixed covariates) vs. Lu 2019 Table 3 (n = 460, 1.8 mg/kg q3w EBE-based)."
)| Cycle | AUC (ng*day/mL) sim | Cmax (ng/mL) sim | Ctrough (ng/mL) sim | AUC (ng*day/mL) published | Cmax (ng/mL) published | Ctrough (ng/mL) published |
|---|---|---|---|---|---|---|
| 1 | NaN +/- NA | 846 +/- 160 | NaN +/- NA | 2,020 +/- 571 | 690 +/- 116 | 13.1 +/- 6.58 |
| 3 | NaN +/- NA | 869 +/- 162 | NaN +/- NA | 2,640 +/- 522 | 713 +/- 117 | 23.7 +/- 10.1 |
| 6 | NaN +/- NA | 670 +/- 107 | 25.8 +/- 13.8 | 2,900 +/- 577 | 721 +/- 118 | 29.3 +/- 12.3 |
Unconjugated MMAE: simulated vs. published
mmae_summary <- summarize_cycle(mmae_nca_long)
mmae_summary_pretty <- mmae_summary |>
transmute(
Cycle = cycle,
`AUC (ng*day/mL) sim` = sprintf("%.1f +/- %.1f", mean_auclast, sd_auclast),
`Cmax (ng/mL) sim` = sprintf("%.2f +/- %.2f", mean_cmax, sd_cmax),
`Ctrough (ng/mL) sim` = sprintf("%.3f +/- %.3f", mean_ctrough, sd_ctrough)
)
published_mmae <- tibble::tibble(
Cycle = factor(c(1, 3, 6), levels = 1:n_cycles),
`AUC (ng*day/mL) published` = c("36.5 +/- 33.9",
"26.4 +/- 24.5",
"25.1 +/- 19.6"),
`Cmax (ng/mL) published` = c("4.08 +/- 3.99",
"2.45 +/- 1.83",
"2.27 +/- 1.57"),
`Ctrough (ng/mL) published` = c("0.269 +/- 0.820",
"0.302 +/- 0.707",
"0.308 +/- 0.527")
)
knitr::kable(
dplyr::left_join(mmae_summary_pretty, published_mmae, by = "Cycle"),
caption = "Unconjugated MMAE NCA -- simulated (200 virtual subjects, mixed covariates) vs. Lu 2019 Table 3 (n = 460, 1.8 mg/kg q3w EBE-based)."
)| Cycle | AUC (ng*day/mL) sim | Cmax (ng/mL) sim | Ctrough (ng/mL) sim | AUC (ng*day/mL) published | Cmax (ng/mL) published | Ctrough (ng/mL) published |
|---|---|---|---|---|---|---|
| 1 | NaN +/- NA | 6.14 +/- 4.12 | NaN +/- NA | 36.5 +/- 33.9 | 4.08 +/- 3.99 | 0.269 +/- 0.820 |
| 3 | NaN +/- NA | 3.62 +/- 1.86 | NaN +/- NA | 26.4 +/- 24.5 | 2.45 +/- 1.83 | 0.302 +/- 0.707 |
| 6 | NaN +/- NA | 3.40 +/- 1.76 | 0.409 +/- 0.395 | 25.1 +/- 19.6 | 2.27 +/- 1.57 | 0.308 +/- 0.527 |
The simulated NCA values are not expected to match published values exactly because:
- The published Table 3 mean +/- SD are over
n = 460actual patients with empirical Bayes estimates of all etas, not over a 200-subject virtual cohort drawn from the prior. - The virtual cohort here uses representative (not paper-replicated) distributions of weight, sex, treatment-naive status, R/G combination, ECOG, etc. Lu 2019’s analysis cohort weights individual patients by their actual covariates; covariates that systematically differ from the reference subject (especially WT, ALB, R/G combo, treatment-naive status) shift the means of these summaries.
- The model omits the eta-on-epsilon residual-error inflation present in the original NONMEM control stream (see Assumptions and deviations below); residual variability is therefore slightly underestimated for highly-variable parameters like CL_t and Cmax.
The cycle-over-cycle structure – acMMAE accumulating roughly 40% from cycle 1 to cycle 6 while MMAE Cmax declines to roughly 56% of its cycle 1 value – is the published model’s primary qualitative claim and is expected to be reproduced.
Assumptions and deviations
Sex reference flip (SEXF vs. source SEX). Lu 2019 NONMEM defines
SEX = SEXN - 1so the sourceSEXindicator is 1 for males. The canonical SEXF reverses the value coding (SEXF = 1 - source_SEX). Multiplicative-ratio effects therefore invert: the paper’stheta24 = 1.20(V1 male:female) becomese_sexf_v1 = 1/1.20 = 0.8333;theta27 = 1.10becomese_sexf_clinf = 1/1.10 = 0.9091;theta39 = 0.911becomese_sexf_frac = 1/0.911 = 1.0977. Effect magnitude and reference subject (male, SEXF = 0) are preserved.ECOG_GE1 reference flip. Lu 2019 NONMEM defines
ECOG0 = 1 if BECOG == 0; the canonical ECOG_GE1 is the complement (ECOG_GE1 = 1 - source_ECOG0). The paper’stheta43 = 0.905(FRAC_NS_ECOG=0 / FRAC_NS_ECOG>=1) becomese_ecog_ge1_frac = 1/0.905 = 1.1050. The reference subject is ECOG_GE1 = 1 (i.e., ECOG >= 1) – consistent with the package’s ECOG_GE1 canonical (reference 0 = “ECOG = 0”).Hepatic-impairment indicator HEPIMP. A new general-scope canonical was registered for the binary NCI ODWG hepatic-impairment indicator (
HEPIMP = 1for groups >= 2 = mild or worse; reference 0 = normal). Source columnBHPTGRPN(categorical 1-4 with 9999 missing sentinel) decomposes toHEPIMP = as.integer(BHPTGRPN > 1.5 & BHPTGRPN != 9999).Anti-CD20 combination indicator COMBO_RG. A new specific-scope canonical was registered for the binary “polatuzumab + rituximab OR obinutuzumab” indicator. The Lu 2019 NONMEM separately defines
RTX = as.integer(COMBO == 1)andGA101 = as.integer(COMBO == 2)and applies effects astheta^(RTX + GA101); because RTX and GA101 are mutually exclusive, RTX+GA101 takes values 0 or 1 and the effect collapses totheta^COMBO_RG. The packaged model takes COMBO_RG as a single indicator; rituximab and obinutuzumab cannot be distinguished.TUMSZ in mm^2 (SPD), not mm. The canonical TUMSZ register pools RECIST sum-of-diameters (mm) and SPD (mm^2 for cHL/NHL) on a single column; for Lu 2019 the unit is mm^2 with reference 5,000 mm^2. The per-model
covariateData[[TUMSZ]]$unitsandnotesfields document the unit choice load-bearingly; users dosing with a TUMSZ in mm need to convert to mm^2 (TUMSZ_mm^2 = sum-of-products) before simulation.B-cell threshold logic. Lu 2019’s CL_INF and CL_T B-cell effects use floored-power forms
BLBCELL^0.0212(with BLBCELL floored at 1) on CL_INF and(BLBCELL/121)^0.578(with the ratio floored at 1) on CL_T. Both flooring rules are implemented viamax(1, .)insidemodel(). For B-cell counts at or below the floor, both effects collapse to 1.Eta-on-epsilon residual error not implemented. The Lu 2019 NONMEM uses a per-individual scaling of residual error
Y = TY * (1 + EPS * exp(ETA10/11))with a 2x2 omega block on ETA10/ETA11 (Table S3 omega(10,10), omega(10,11), omega(11,11) = 0.0521, 0.038, 0.0427). nlmixr2lib does not natively support eta-on-epsilon; the packaged model collapses to a fixed proportional residual error per analyte using the Sigma point estimates (Sigma11 = 0.0254 -> CcpropSd = 0.1594; Sigma22 = 0.0726 -> CmmaepropSd = 0.2694). This slightly under-estimates residual variability for individuals with large positive ETA10/ETA11 and over-estimates for those with large negative values, but does not bias the typical-value parameters or the IIV terms.Time variable.
timein rxode2 corresponds to the NONMEMTin the $DES block (time since first dose / start of integration). For the CL_NS Hill function and FRAC_NS time-decay, repeated dosing of multiple patients is handled by setting up dose events at a common time origin;timeis not reset at each dose. This matches the Lu 2019 model’s intent: time-decaying clearance and conversion-fraction effects are cumulative across cycles.Reference subject. All covariate-effect ratios collapse to 1 when WT = 75 kg, ALB = 35 g/L, TUMSZ = 5,000 mm^2, BLBCELL = 1 cell/uL, SEXF = 0 (male), LINE_1L = 0 (R/R), RACE_ASIAN = 0, COMBO_RG = 0 (single agent), HEPIMP = 0 (normal), ECOG_GE1 = 1 (ECOG >= 1), so the typical-value parameters in Table 1 directly apply.
Race distribution. Lu 2019 reports only the Asian indicator as retained in the final model (theta25). The 200-subject virtual cohort uses 15% Asian / 85% non-Asian, with race not finer-grained.
Treatment-naive distribution. In the Lu 2019 cohort, the only exclusively first-line study was GO29044 (n = 45 of 460); the rest enrolled R/R patients. The virtual cohort uses 10% naive / 90% R/R, approximating the pooled mixture.
Programmatic access
mod_meta <- rxode2::rxode(readModelDb("Lu_2019_polatuzumab"))
#> ℹ parameter labels from comments will be replaced by 'label()'
str(mod_meta$meta$population, max.level = 1)
#> List of 13
#> $ n_subjects : int 460
#> $ n_studies : int 4
#> $ n_observations : chr "4215 acMMAE + 4194 unconjugated MMAE concentration-time pairs (Lu 2019 Results section first paragraph)"
#> $ age_range : chr "Adults with NHL (Lu 2019 does not tabulate age in the main paper; the four constituent studies enrolled adult p"| __truncated__
#> $ weight_range : chr "5th-95th percentile 48.7-118 kg per Lu 2019 Figure 3 sensitivity-analysis annotation; reference 75 kg used for "| __truncated__
#> $ sex_female_pct : num NA
#> $ race_ethnicity : chr "Tested as Asian vs non-Asian indicator only in the final model (RACE_ASIAN); a multiplicative effect on V1 (e_a"| __truncated__
#> $ disease_state : chr "Relapsed/refractory or previously untreated B-cell non-Hodgkin lymphoma (NHL): diffuse large B-cell lymphoma (D"| __truncated__
#> $ dose_range : chr "Pola 0.1-2.4 mg/kg IV every 3 weeks (Q3W) as monotherapy or in combination with rituximab, obinutuzumab, bendam"| __truncated__
#> $ regions : chr "Multi-regional (the four constituent studies were global Phase I/Ib/II trials NCT01290549, NCT01691898, NCT0225"| __truncated__
#> $ studies : chr "DCS4968g (NCT01290549, Phase I/Ib single-agent and Pola+R run-in), GO27834 / ROMULUS (NCT01691898, Phase Ib/II "| __truncated__
#> $ reference_subject: chr "75 kg, ALB 35 g/L, TUMSZ 5000 mm^2 SPD, B-cell 1 cell/uL (so max(1, BLBCELL) = 1), male, R/R, non-Asian, normal"| __truncated__
#> $ notes : chr "Population characteristics drawn from Lu 2019 main text Results, Figure 3 sensitivity-analysis annotations, and"| __truncated__
str(mod_meta$meta$covariateData, max.level = 1)
#> List of 10
#> $ WT :List of 6
#> $ SEXF :List of 6
#> $ LINE_1L :List of 6
#> $ RACE_ASIAN:List of 6
#> $ ALB :List of 6
#> $ BLBCELL :List of 6
#> $ TUMSZ :List of 6
#> $ ECOG_GE1 :List of 6
#> $ HEPIMP :List of 6
#> $ COMBO_RG :List of 6