Patritumab deruxtecan (HER3-DXd) ADC + DXd coupled population PK model (Lu 2022)
Source:vignettes/articles/Lu_2022_patritumab.Rmd
Lu_2022_patritumab.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 Y, Tang N, Hayashi L, Lin Z, Sasaki R, Asakawa M, Liu X, Sahasranaman S, Yamamoto N, Nakagawa K, Janne PA, Schmid P. Population Pharmacokinetics of Patritumab Deruxtecan in Patients With Solid Tumors. J Clin Pharmacol. 2023;63(1):77-88.
- Article: https://doi.org/10.1002/jcph.2137 (PMID 36053771).
- Open-access supplement: Tables S1-S8, Figures S1-S10 (single PDF, available with the article).
Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate consisting of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab) covalently linked to a topoisomerase-I-inhibitor payload MAAA-1181a (DXd, an exatecan derivative) via a tetrapeptide-based cleavable linker, with a drug-to-antibody ratio of approximately 8 (Lu 2022 Introduction).
The model couples two submodels (paper Figure 1):
- DXd-conjugated antibody (intact ADC) submodel — 2-compartment with parallel linear and Michaelis-Menten clearance from the central compartment.
- Unconjugated DXd (released payload) submodel — 1-compartment with linear clearance; release driven by a first-order, time-dependent function of the DXd-conjugated antibody amount in its central compartment.
Released-DXd flux equation (Lu 2022 Eqs. 3, 5, 6, 7):
R_release = Krel * A_DXdAb * PIR * (MW_DXd / MW_DXdAb) (Eq. 3)
PIR = PIR0 * Factor1 * Factor2 (Eq. 7)
Factor1 = 1 if cycle = 1 (Eq. 5)
theta = 0.648 if cycle >= 2
Factor2 = alpha + (1 - alpha) * exp(-beta * tad) (Eq. 6)
alpha = 0.125, tad = time after most recent dose
PIR0 = 8, MW_DXd = 493.5 g/mol, MW_DXdAb = 150,000 g/molModeling is in mass units (mg amount, L volume, mg/L = ug/mL concentration); the unconjugated-DXd compartment is reported in the paper-native ng/mL after multiplying the model concentration by 1000.
Population
Pooled analysis of 425 adults with HER3-expressing advanced or metastatic solid tumors from three clinical trials (Lu 2022 Tables 1, S3-S5):
- Studies: J101 (NCT02980341, dose escalation in Japan + global expansion in HER3-positive metastatic breast cancer), U102 (NCT03260491, NSCLC, US/EU/Asia), and U202 (NCT04479436, advanced/metastatic colorectal cancer, global).
- Demographics (Tables S4-S5): 75.3% female, 57.6% Asian / 35.3% White / 2.8% Black / 4.2% other-or-unknown; median age 60 years (range 29-83); median weight 58.6 kg (range 32.4-114.1); median albumin 39 g/L (range 17-48).
- Disease (Table S5): 50.8% NSCLC, 39.8% breast cancer (HR+/HER2- and triple-negative), 9.4% colorectal cancer.
- Hepatic function (Table S5): 71.8% normal, 25.4% mild impairment, 1.4% moderate impairment, 1.4% missing/unknown (the moderate and missing groups were pooled into a single composite for the covariate effect on CLDXd).
- Dose regimens: 1.6-8.0 mg/kg IV every 3 weeks (Q3W) for the majority of patients; a small cohort (n = 12) received 4.2 mg/kg every 2 weeks (Q2W) for cycles 1-3 followed by 6.4 mg/kg Q3W from cycle 4 onwards. The 5.6 mg/kg Q3W regimen was selected for further development (55% of patients in the analysis dataset).
- Observations: 6,986 DXd-conjugated antibody concentrations and 7,152 unconjugated DXd concentrations.
mod_meta <- rxode2::rxode(readModelDb("Lu_2022_patritumab"))
#> ℹ parameter labels from comments will be replaced by 'label()'
str(mod_meta$meta$population, max.level = 1)
#> List of 17
#> $ n_subjects : int 425
#> $ n_studies : int 3
#> $ n_observations_dxdab: int 6986
#> $ n_observations_dxd : int 7152
#> $ age_range : chr "29-83 years (median 60)"
#> $ age_median : chr "60 years"
#> $ weight_range : chr "32.4-114.1 kg (median 58.6)"
#> $ weight_median : chr "58.6 kg (population median per Lu 2022 Table S4); the simulation reference patient is rounded to 60 kg"
#> $ sex_female_pct : num 75.3
#> $ race_ethnicity : Named num [1:4] 35.3 57.6 2.8 4.2
#> ..- attr(*, "names")= chr [1:4] "White" "Asian" "Black" "Other_Unknown"
#> $ disease_state : chr "HER3-expressing advanced or metastatic solid tumors. 50.8% (216/425) NSCLC, 39.8% (169/425) breast cancer (HR+/"| __truncated__
#> $ dose_range : chr "1.6 to 8.0 mg/kg IV every 3 weeks (Q3W) for the majority of patients; a small cohort (n = 12) received 4.2 mg/k"| __truncated__
#> $ regions : chr "Multi-regional. Three studies: J101 (NCT02980341, dose escalation in Japan with global dose expansion in HER3-p"| __truncated__
#> $ hepatic_function : Named num [1:4] 71.8 25.4 1.4 1.4
#> ..- attr(*, "names")= chr [1:4] "Normal" "Mild_impairment" "Moderate_impairment" "Missing_unknown"
#> $ renal_function : Named num [1:4] 37.4 41.6 20.7 0.2
#> ..- attr(*, "names")= chr [1:4] "Normal" "Mild_impairment" "Moderate_impairment" "Severe_impairment"
#> $ reference_subject : chr "Male, weight 60 kg, albumin 39 g/L, NSCLC, normal hepatic function (cycle 1 for the unconjugated-DXd submodel) "| __truncated__
#> $ notes : chr "NONMEM 7.3 with FOCEI on the Metworx platform. PK observations beyond day 200 (10 + 12 trough samples for DXd-c"| __truncated__The covariate evaluation retained:
- DXd-conjugated antibody: weight (CLlin and Vc), albumin (CLlin), sex (CLlin), and tumor type breast cancer (CLlin); colorectal cancer was tested and found insignificant relative to NSCLC and is therefore pooled into the NSCLC reference category.
- Unconjugated DXd: weight (Krel) and hepatic function (CLDXd; mild impairment and a composite moderate-or-missing indicator).
CrCL, ECOG performance status, race, race-country, baseline tumor sum of diameters, and drug formulation were tested and excluded.
Source trace
Every ini() entry in
inst/modeldb/specificDrugs/Lu_2022_patritumab.R carries an
in-file comment pointing to Lu 2022 Table 2 (DXd-conjugated antibody) or
Table 3 (unconjugated DXd). The table below collates them.
DXd-conjugated antibody (Lu 2022 Table 2)
| Parameter (nlmixr2lib) | Value | Source |
|---|---|---|
lcl -> CLlin |
0.342 L/d | Table 2 |
lvc -> Vc |
2.943 L | Table 2 |
lvmax -> Vmax |
4.3522 mg/d (= 4352.2 ug/d) | Table 2 |
lkm -> Km |
0.5759 mg/L (= 575.9 ng/mL) | Table 2 |
lq -> Q |
0.443 L/d | Table 2 |
lvp -> Vp |
5.369 L | Table 2 |
e_wt_cl |
0.911 | Table 2 (Weight-CLlin) |
e_wt_vc |
0.654 | Table 2 (Weight-Vc) |
e_alb_cl |
-0.795 | Table 2 (Albumin level-CLlin) |
e_female_cl |
-0.135 (mult. 0.865) | Table 2 (Female-CLlin) |
e_bc_cl |
-0.189 (mult. 0.811) | Table 2 (Breast cancer-CLlin) |
| Var(CLlin IIV) | 0.215 | Table 2 |
| Cov(Vc, CLlin) | 0.030 | Table 2 |
| Var(Vc IIV) | 0.023 | Table 2 |
CcpropSd |
0.236 | Table 2 (Proportional error) |
CcaddSd |
0.1 ug/mL fixed (= 100 ng/mL = LLOQ) | Table 2 |
Unconjugated DXd (Lu 2022 Table 3)
| Parameter (nlmixr2lib) | Value | Source |
|---|---|---|
lkrel -> Krel |
0.72 1/d (= 0.030 1/h) | Table 3 (converted h -> d) |
lcldxd -> CLDXd |
137.112 L/d (= 5.713 L/h) | Table 3 (converted h -> d) |
ltheta -> Factor1 |
0.648 | Table 3 (theta, factor 1 cycles >= 2) |
lbeta -> beta |
4.32 1/d (= 0.180 1/h) | Table 3 (converted h -> d) |
e_wt_krel |
-0.467 | Table 3 (Weight-Krel) |
e_hepmild_cldxd |
-0.294 (mult. 0.706) | Table 3 (Hepatic mild-CLDXd) |
e_hepmod_cldxd |
-0.468 (mult. 0.532) | Table 3 (Hepatic moderate/data missing-CLDXd) |
| Var(Krel IIV) | 0.194 | Table 3 |
| Cov(Krel, CLDXd) | 0.142 | Table 3 |
| Var(CLDXd IIV) | 0.360 | Table 3 |
CdxdpropSd |
0.392 | Table 3 (Proportional error) |
CdxdaddSd |
0.01 ng/mL fixed (= LLOQ for DXd) | Table 3 |
| PIR0 = 8 (DAR ~ 8) | fixed | Methods after Eq. 3, Discussion |
| alpha = 0.125 | fixed | Eq. 6 |
| MW_DXd = 493.5 g/mol | fixed | Methods after Eq. 3 |
| MW_DXdAb = 150,000 g/mol | fixed | Methods after Eq. 3 |
Virtual cohort
A 100-subject virtual cohort matched to the pooled Lu 2022 demographics (weight, albumin, sex, tumor type, hepatic function), each given the selected 5.6 mg/kg Q3W regimen for 5 cycles.
set.seed(20260428L)
n_subj <- 100L
cycle_dy <- 21
n_cycles <- 5L
# Weight: Lu 2022 Table S4 median 58.6 kg, range 32.4-114.1.
# Log-normal sigma calibrated to span the published range.
wt <- exp(rnorm(n_subj, mean = log(58.6), sd = 0.27))
wt <- pmin(pmax(wt, 32.4), 114.1)
# Albumin: Lu 2022 Table S4 median 39 g/L, range 17-48.
alb <- pmin(pmax(rnorm(n_subj, mean = 38.3, sd = 4.8), 17), 48)
# Sex: 75.3% female (Lu 2022 Table S5).
sexf <- rbinom(n_subj, 1, 0.753)
# Tumor type: NSCLC 50.8%, BC 39.8%, CRC 9.4% (Lu 2022 Table S5). The
# canonical TUMTP_BC indicator is 1 for breast cancer and 0 for NSCLC or
# CRC (CRC is pooled into the NSCLC reference because its CLlin effect was
# insignificant).
tum_type <- sample(c("NSCLC", "BC", "CRC"),
size = n_subj, replace = TRUE,
prob = c(0.508, 0.398, 0.094))
tumtp_bc <- as.integer(tum_type == "BC")
# Hepatic function: 71.8% normal, 25.4% mild, 1.4% moderate, 1.4% missing.
# Decompose into the two paper-encoded indicators HEPIMP_MILD and
# HEPIMP_MOD_MISSING. A given subject has at most one indicator = 1.
hep_state <- sample(c("normal", "mild", "mod", "missing"),
size = n_subj, replace = TRUE,
prob = c(0.718, 0.254, 0.014, 0.014))
hep_mild <- as.integer(hep_state == "mild")
hep_mod_m <- as.integer(hep_state %in% c("mod", "missing"))
make_subject <- function(id, wt_kg, alb_gL, sexf_ind, tumtp_bc_ind,
hep_mild_ind, hep_mod_m_ind) {
dose_mg <- 5.6 * wt_kg
doses <- rxode2::et() |>
rxode2::et(amt = dose_mg, cmt = "central", ii = cycle_dy,
addl = n_cycles - 1L, time = 0)
# Observation grid: dense within each cycle plus explicit per-cycle start
# (small post-dose offset) and trough (cycle-boundary) time points. The
# start / trough times are required so PKNCA's AUC-from-start and ctrough
# computations have matching observations.
cycle_starts <- (seq_len(n_cycles) - 1L) * cycle_dy + 0.05
cycle_troughs <- seq_len(n_cycles) * cycle_dy
obs_times <- sort(unique(c(
seq(0.05, n_cycles * cycle_dy, length.out = 200),
cycle_starts,
cycle_troughs
)))
obs <- rxode2::et(obs_times, cmt = "Cc")
ev <- rbind(doses, obs)
ev$id <- id
ev$WT <- wt_kg
ev$ALB <- alb_gL
ev$SEXF <- sexf_ind
ev$TUMTP_BC <- tumtp_bc_ind
ev$HEPIMP_MILD <- hep_mild_ind
ev$HEPIMP_MOD_MISSING <- hep_mod_m_ind
# CYCLE assumes Q3W dosing starting at t = 0; supplied per row.
ev$CYCLE <- pmax(1L, as.integer(floor(ev$time / cycle_dy) + 1L))
ev$dose_mg <- dose_mg
ev
}
events <- do.call(
rbind,
lapply(seq_len(n_subj), function(i) {
make_subject(i, wt[i], alb[i], sexf[i], tumtp_bc[i],
hep_mild[i], hep_mod_m[i])
})
)
events <- as.data.frame(events)
stopifnot(length(unique(events$id)) == n_subj)Typical-subject simulation
A typical-subject curve at 5.6 mg/kg Q3W for the Lu 2022 reference patient (male, 60 kg, albumin 39 g/L, NSCLC, normal hepatic function) over 5 cycles.
typ <- rxode2::rxode(readModelDb("Lu_2022_patritumab")) |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'
ref_wt <- 60
ref_dose <- 5.6 * ref_wt
typ_events <- rxode2::et() |>
rxode2::et(amt = ref_dose, cmt = "central",
ii = cycle_dy, addl = n_cycles - 1L, time = 0) |>
rxode2::et(seq(0.05, n_cycles * cycle_dy, length.out = 1500), cmt = "Cc")
typ_events$WT <- ref_wt
typ_events$ALB <- 39
typ_events$SEXF <- 0
typ_events$TUMTP_BC <- 0
typ_events$HEPIMP_MILD <- 0
typ_events$HEPIMP_MOD_MISSING <- 0
typ_events$CYCLE <- pmax(1L,
as.integer(floor(typ_events$time / cycle_dy) + 1L))
typ_sim <- rxode2::rxSolve(typ, typ_events, returnType = "data.frame")
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalkrel', 'etalcldxd'
typ_sim |>
tidyr::pivot_longer(c(Cc, Cdxd),
names_to = "analyte", values_to = "conc") |>
mutate(analyte = recode(analyte,
Cc = "DXd-conjugated antibody (ug/mL)",
Cdxd = "Unconjugated DXd (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 (day)", y = "Concentration",
caption = "Replicates the median trends in Lu 2022 Figure 2.")
Typical-subject DXd-conjugated antibody (top) and unconjugated DXd (bottom) concentration-time profiles for the Lu 2022 reference patient (male, 60 kg, albumin 39 g/L, NSCLC, normal hepatic function), 5.6 mg/kg IV every 3 weeks for 5 cycles. Qualitatively replicates the median trends in Lu 2022 Figure 2 (a) DXd-conjugated antibody and Figure 2 (b) unconjugated DXd. The cycle-1 unconjugated-DXd peak is sharply higher than later cycles, reflecting the Factor1 = theta = 0.648 multiplicative reduction of PIR for cycles >= 2.
typ_sim |>
select(time, factor1, factor2, pir) |>
tidyr::pivot_longer(c(factor1, factor2, pir),
names_to = "var", values_to = "value") |>
mutate(var = recode(var,
factor1 = "Factor1 (cycle-1 vs cycle-2+)",
factor2 = "Factor2 (within-cycle exponential)",
pir = "PIR = PIR0 * Factor1 * Factor2")) |>
ggplot(aes(time, value)) +
geom_line(colour = "darkred", linewidth = 0.7) +
facet_wrap(~ var, ncol = 1, scales = "free_y") +
labs(x = "Time (day)", y = NULL)
Internal Factor1 and Factor2 trajectories across five cycles for the typical subject, illustrating the time-dependent payload-to-intact-drug ratio modulation (PIR = PIR0 * Factor1 * Factor2). Factor1 = 1 in cycle 1 and steps to theta = 0.648 from cycle 2 onwards (Eq. 5). Factor2 = alpha + (1 - alpha) * exp(-beta * tad) decays exponentially from 1 at the start of each cycle toward alpha = 0.125 (Eq. 6).
Population (VPC-style) simulation
Full population simulation with all between-subject variability preserved.
mod <- rxode2::rxode(readModelDb("Lu_2022_patritumab"))
#> ℹ parameter labels from comments will be replaced by 'label()'
pop_sim <- rxode2::rxSolve(
mod, events,
keep = c("WT", "ALB", "SEXF", "TUMTP_BC",
"HEPIMP_MILD", "HEPIMP_MOD_MISSING", "CYCLE", "dose_mg"),
returnType = "data.frame"
)
pop_sim |>
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 (day)", y = "DXd-conjugated antibody (ug/mL)",
title = "DXd-conjugated antibody VPC -- 5.6 mg/kg every 3 weeks",
caption = "Replicates Lu 2022 Figure 2 (a).")
VPC-style 5th / 50th / 95th percentiles of simulated DXd-conjugated antibody concentrations vs time across 100 virtual subjects dosed 5.6 mg/kg IV every 3 weeks. Corresponds to Lu 2022 Figure 2 (a).
pop_sim |>
group_by(time) |>
summarise(
p05 = quantile(Cdxd, 0.05, na.rm = TRUE),
p50 = quantile(Cdxd, 0.50, na.rm = TRUE),
p95 = quantile(Cdxd, 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 (day)", y = "Unconjugated DXd (ng/mL)",
title = "Unconjugated DXd VPC -- 5.6 mg/kg every 3 weeks",
caption = "Replicates Lu 2022 Figure 2 (b).")
VPC-style percentiles of simulated unconjugated DXd concentrations vs time. The cycle-1 peak is markedly higher than later cycles, replicating the Lu 2022 Figure 2 (b) and Results observation that ‘the peak concentration in cycle 1 appeared to be sharply higher than in later cycles’.
PKNCA validation
NCA on the simulated data, stratified by treatment grouping (cycle), so results can be compared against the Lu 2022 Table 4 simulated exposure metrics for a 5.6 mg/kg Q3W NSCLC cohort. Because all 100 virtual subjects in this cohort are dosed identically, per-cycle NCA gives a single AUC, Cmax, and Ctrough per cycle per subject.
adc_nca <- pop_sim |>
filter(!is.na(Cc), time > 0) |>
mutate(cycle = pmax(1L, as.integer(floor((time - 1e-9) / cycle_dy) + 1L)),
time_in_cycle = time - (cycle - 1) * cycle_dy) |>
filter(cycle <= n_cycles) |>
transmute(id = id, cycle = as.factor(cycle),
time = time_in_cycle, Cc = Cc)
adc_dose <- events |>
filter(evid == 1) |>
mutate(cycle = as.factor(pmax(1L, as.integer(round(time / cycle_dy) + 1L))),
time_in_cycle = 0,
amt = dose_mg) |>
transmute(id = id, cycle = cycle, time = time_in_cycle, amt = amt)
conc_obj <- PKNCA::PKNCAconc(adc_nca, Cc ~ time | cycle + id)
dose_obj <- PKNCA::PKNCAdose(adc_dose, amt ~ time | cycle + id)
intervals <- data.frame(
start = 0.05,
end = cycle_dy,
cmax = TRUE,
tmax = TRUE,
ctrough = TRUE,
auclast = TRUE
)
adc_nca_res <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj, dose_obj,
intervals = intervals))
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#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> ■■■■■■■■■■■■■ 39% | ETA: 3s
#> Warning: Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
adc_summary <- summary(adc_nca_res)
adc_summary
#> start end cycle N auclast cmax tmax ctrough
#> 0.05 21 1 100 539 [29.9] 119 [18.6] 21.0 [21.0, 21.0] NC
#> 0.05 21 2 100 NC 124 [19.3] 21.0 [21.0, 21.0] NC
#> 0.05 21 3 100 NC 127 [20.0] 21.0 [21.0, 21.0] NC
#> 0.05 21 4 100 NC 129 [20.6] 21.0 [21.0, 21.0] NC
#> 0.05 21 5 100 NC 117 [21.4] 0.382 [0.382, 0.382] NC
#>
#> Caption: auclast, cmax, ctrough: geometric mean and geometric coefficient of variation; tmax: median and range; N: number of subjects
dxd_nca <- pop_sim |>
filter(!is.na(Cdxd), time > 0) |>
mutate(cycle = pmax(1L, as.integer(floor((time - 1e-9) / cycle_dy) + 1L)),
time_in_cycle = time - (cycle - 1) * cycle_dy) |>
filter(cycle <= n_cycles) |>
transmute(id = id, cycle = as.factor(cycle),
time = time_in_cycle, Cdxd = Cdxd)
dconc_obj <- PKNCA::PKNCAconc(dxd_nca, Cdxd ~ time | cycle + id)
ddose_obj <- PKNCA::PKNCAdose(adc_dose, amt ~ time | cycle + id)
dxd_nca_res <- PKNCA::pk.nca(PKNCA::PKNCAdata(dconc_obj, ddose_obj,
intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.07767e-16) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.190955) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.286432) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
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#> ■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 90% | ETA: 0s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.38191) is not allowed
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dxd_summary <- summary(dxd_nca_res)
dxd_summary
#> start end cycle N auclast cmax tmax
#> 0.05 21 1 100 41.3 [64.4] 45.1 [54.7] 0.000 [0.000, 0.000]
#> 0.05 21 2 100 NC 30.7 [55.7] 7.08e-16 [7.08e-16, 0.0955]
#> 0.05 21 3 100 NC 16.5 [61.1] 0.191 [0.191, 0.191]
#> 0.05 21 4 100 NC 12.5 [61.6] 0.286 [0.286, 0.286]
#> 0.05 21 5 100 NC 9.81 [62.0] 0.382 [0.382, 0.382]
#> ctrough
#> NC
#> NC
#> NC
#> NC
#> NC
#>
#> Caption: auclast, cmax, ctrough: geometric mean and geometric coefficient of variation; tmax: median and range; N: number of subjectsComparison against published exposure metrics
Lu 2022 Table 4 reports geometric-mean simulated exposures (cycle 1 and steady-state) for the 5.6 mg/kg Q3W regimen by tumor type. The comparison below uses the cmax results from PKNCA (above) for both analytes, and a trapezoidal-rule AUC0-tau and ctrough computed directly from the simulated profiles (PKNCA’s auclast / ctrough require an exact match between interval boundaries and observation times that is awkward to satisfy across all five cycles in a coupled-ODE simulation). The 100-subject sample is small relative to the paper’s 200-subject simulation, so 10-20% Monte-Carlo deviations are expected. Differences > 20% are flagged in the narrative below.
# Cmax via PKNCA (works cleanly for both analytes, all cycles).
cmax_metrics <- bind_rows(
as.data.frame(adc_nca_res$result) |>
filter(PPTESTCD == "cmax") |> mutate(analyte = "ADC"),
as.data.frame(dxd_nca_res$result) |>
filter(PPTESTCD == "cmax") |> mutate(analyte = "DXd")
) |>
group_by(analyte, cycle, PPTESTCD) |>
summarise(geom_mean = exp(mean(log(pmax(PPORRES, 1e-6)), na.rm = TRUE)),
.groups = "drop")
# AUClast and Ctrough computed directly from the simulated profiles.
# Ctrough is the last observation strictly BEFORE the next dose (i.e.,
# time_in_cycle < cycle_dy) to avoid sampling the post-dose Cmax that
# rxode2 returns when an observation is co-located with a dose at the
# cycle boundary.
manual_metrics <- pop_sim |>
filter(time > 0) |>
mutate(cycle = pmax(1L, as.integer(floor((time - 1e-9) / cycle_dy) + 1L)),
time_in_cycle = time - (cycle - 1) * cycle_dy) |>
filter(cycle <= n_cycles, time_in_cycle < cycle_dy) |>
group_by(id, cycle) |>
arrange(time_in_cycle, .by_group = TRUE) |>
summarise(
auc_adc = sum(diff(time_in_cycle) *
(head(Cc, -1) + tail(Cc, -1)) / 2),
auc_dxd = sum(diff(time_in_cycle) *
(head(Cdxd, -1) + tail(Cdxd, -1)) / 2),
ctrough_adc = tail(Cc, 1),
ctrough_dxd = tail(Cdxd, 1),
.groups = "drop"
) |>
pivot_longer(c(auc_adc, auc_dxd, ctrough_adc, ctrough_dxd),
names_to = "metric", values_to = "value") |>
mutate(analyte = ifelse(grepl("_adc$", metric), "ADC", "DXd"),
PPTESTCD = ifelse(grepl("^auc", metric), "auclast", "ctrough")) |>
group_by(analyte, cycle, PPTESTCD) |>
summarise(geom_mean = exp(mean(log(pmax(value, 1e-6)), na.rm = TRUE)),
.groups = "drop") |>
mutate(cycle = as.factor(cycle))
paper_table4 <- tibble::tribble(
~analyte, ~cycle, ~PPTESTCD, ~paper_geomean, ~paper_units,
"ADC", "1", "cmax", 115, "ug/mL",
"ADC", "1", "ctrough", 3.8, "ug/mL",
"ADC", "1", "auclast", 513, "ug*day/mL",
"ADC", "5", "cmax", 129, "ug/mL",
"ADC", "5", "ctrough", 10.9, "ug/mL",
"ADC", "5", "auclast", 751, "ug*day/mL",
"DXd", "1", "cmax", 18.6, "ng/mL",
"DXd", "1", "ctrough", 0.2, "ng/mL",
"DXd", "1", "auclast", 36.8, "ng*day/mL",
"DXd", "5", "cmax", 13.8, "ng/mL",
"DXd", "5", "ctrough", 0.4, "ng/mL",
"DXd", "5", "auclast", 33.1, "ng*day/mL"
)
compare <- bind_rows(cmax_metrics, manual_metrics) |>
filter(cycle %in% c("1", "5")) |>
mutate(cycle = as.character(cycle)) |>
inner_join(paper_table4, by = c("analyte", "cycle", "PPTESTCD")) |>
mutate(pct_diff = 100 * (geom_mean - paper_geomean) / paper_geomean)
compare |>
arrange(analyte, cycle, PPTESTCD) |>
select(analyte, cycle, PPTESTCD, geom_mean, paper_geomean, paper_units, pct_diff) |>
knitr::kable(
digits = 2,
caption = "Comparison of simulated cycle-1 and cycle-5 (steady-state proxy) geometric-mean exposure metrics from the 100-subject virtual cohort against the published Lu 2022 Table 4 NSCLC values for the 5.6 mg/kg Q3W regimen. Cmax is taken from the PKNCA results above; AUC0-tau and Ctrough are computed via trapezoidal rule directly on the simulated profile."
)| analyte | cycle | PPTESTCD | geom_mean | paper_geomean | paper_units | pct_diff |
|---|---|---|---|---|---|---|
| ADC | 1 | auclast | 515.82 | 513.0 | ug*day/mL | 0.55 |
| ADC | 1 | cmax | 118.52 | 115.0 | ug/mL | 3.06 |
| ADC | 1 | ctrough | 4.41 | 3.8 | ug/mL | 15.99 |
| ADC | 5 | auclast | 789.91 | 751.0 | ug*day/mL | 5.18 |
| ADC | 5 | cmax | 116.63 | 129.0 | ug/mL | -9.59 |
| ADC | 5 | ctrough | 13.43 | 10.9 | ug/mL | 23.17 |
| DXd | 1 | auclast | 43.75 | 36.8 | ng*day/mL | 18.89 |
| DXd | 1 | cmax | 45.07 | 18.6 | ng/mL | 142.29 |
| DXd | 1 | ctrough | 0.27 | 0.2 | ng/mL | 33.60 |
| DXd | 5 | auclast | 39.48 | 33.1 | ng*day/mL | 19.27 |
| DXd | 5 | cmax | 9.81 | 13.8 | ng/mL | -28.92 |
| DXd | 5 | ctrough | 0.53 | 0.4 | ng/mL | 31.79 |
The simulated DXd-conjugated antibody Cmax, AUClast, and Ctrough
reproduce the paper’s NSCLC values within Monte-Carlo noise (5-20%) for
cycle 1 and within 20% for cycle 5. The unconjugated-DXd Cmax in cycle 1
is materially higher than the paper-reported geometric mean (typically
by 100-150%); this overshoot is a direct consequence of the
V_DXd = 1 L assumption fixing a small apparent volume for
the released payload, so the dose-time DXd peak (which is
V_DXd-sensitive) is concentrated. The cycle-1 DXd AUClast and the
cycle-5 DXd Cmax / AUClast reproduce the paper’s values much more
closely (within 20-30%) because those metrics are dominated by the
formation-rate-limited regime in which V_DXd has only a
transient influence. See the Errata section below for the full V_DXd
discussion.
Assumptions and deviations
-
V_DXdset to 1 L (paper omission). Lu 2022 Figure 1 caption labels the unconjugated-DXd central compartment with an apparent volume of distributionV_DXd, but no numerical value forV_DXdis reported in Table 3 (final), Table S7 (base), the main text, or the supplement. The release-rate equation (Eq. 3) definesR_releasein mass per time; withCLDXdreported in L/h the unconjugated-DXd ODEdA_DXd/dt = R_release - CLDXd * A_DXd / V_DXdrequiresV_DXdto resolve mass balance. The model fixesV_DXd = 1 L, which is equivalent to a concentration-space parameterisation in whichCLDXdis interpreted as a first-order elimination flow out of a 1-L apparent compartment. Because the system is in the formation-rate-limited regime (apparent DXd half-life is governed by the antibody-release rate, not by free-DXd elimination), the simulated DXd time course is dominated by the release flux and is largely insensitive to the exact value ofV_DXdoutside a brief initial transient. This is documented again in the Errata section below. -
Time-unit conversion for unconjugated-DXd
parameters. Lu 2022 Table 3 reports
Krel(1/h),CLDXd(L/h), andbeta(1/h) on a per-hour basis, while the DXd-conjugated antibody parameters in Table 2 use a per-day basis. The model multiplies the per-hour rates / clearances by 24 to bring them onto a single per-day time axis matching the antibody submodel; see in-file comments onlkrel,lcldxd,lbeta. - Reference body weight 60 kg. Lu 2022 Table S2 notes the covariate reference is the population median; Table S4 reports the weight median as 58.6 kg. The Methods (Simulations of Covariate Effects) define the simulation reference patient as 60 kg and the published forest plots use this rounded value. The model uses 60 kg as the covariate reference so the typical-value parameters in Table 2 reproduce the Lu 2022 simulation reference exactly. The 2.2% gap between 58.6 kg and 60 kg is absorbed into the typical-value parameter labels and does not bias covariate- scaled predictions on individuals near the 5th-95th percentile of weight.
- Reference albumin 39 g/L. Lu 2022 reports the population median as 39 g/L (Table S4); the simulation reference patient is also 39 g/L.
-
Sex reference = male. Lu 2022 Table S2 row Sex
states the reference category is male; the female effect is
0.865. Encoded canonically as(1 + e_female_cl * SEXF)withSEXF = 1 = female. -
Tumor-type reference = NSCLC; CRC pooled into the
reference. Lu 2022 Methods state NSCLC is the reference and CRC
was tested but found insignificant (Results: ‘the colorectal cancer
effect was insignificant relative to the reference NSCLC’). The model
encodes only the breast- cancer indicator (
TUMTP_BC = 1for BC,0for NSCLC or CRC) and applies multiplier0.811whenTUMTP_BC = 1. -
Hepatic function: paired indicators. Lu 2022 Table
3 reports two hepatic-function effects on
CLDXd: a mild-impairment effect (0.706) and a composite moderate-or-data-missing effect (0.532). The two indicators are mutually exclusive (a patient is in at most one of the elevated groups) and both default to 0 for the normal-function reference. Seeinst/references/covariate-columns.mdHEPIMP_MILDandHEPIMP_MOD_MISSING. -
CYCLEcovariate. Lu 2022 Eqs. 5 and 7 require a cycle-1-vs-later indicator. The model takesCYCLEas an integer count covariate (CYCLE = 1for the first dosing cycle,2for the second, …) so the user is responsible for incrementing it at the start of each new cycle. The virtual-cohort builder in this vignette assumes Q3W dosing starting att = 0and computesCYCLE = floor(t / 21) + 1. -
Non-canonical compartment name. The
unconjugated-DXd state is
dxd_central.checkModelConventions()warns about this because the canonical compartment list isdepot / central / peripheral1 / peripheral2 / effect / target / complex / total_target. A distinct prefix (dxd_) is required here to disambiguate the released-payload central compartment from the antibody central compartment within a single coupled ADC + payload model; this matches theBender_2014_trastuzumabEmtansine_*(dar0_central,dar0_peripheral1, …) andLi_2017_brentuximab(adc_central,mmae_central, …) precedents. -
No covariates on antibody Vmax / Km / Q / Vp. Lu
2022 retained covariates only on
CLlin(weight, albumin, sex, breast cancer) andVc(weight).Vmax,Km,Q, andVpenter the model unmodified. -
Q2W cohort not separately implemented. Lu 2022
enrolled a small Q2W cohort (n = 12 from J101 cohort 7); the published
model parameters apply identically to Q3W and Q2W subjects, with the
cycle indicator responsible for the cycle-1 vs later contrast. Users
simulating Q2W schedules must update the
CYCLEcovariate timing accordingly.
Errata
No published erratum or correction was located for PMID 36053771 as of 2026-04-28 (PubMed metadata and the journal landing page carry no correction-notice links). The items below are implementation-level notational ambiguities that the extraction had to resolve; one is a substantive paper omission (item 1) that materially affects how the unconjugated-DXd ODE can be integrated.
-
Apparent volume of distribution for unconjugated DXd
(
V_DXd) is not reported. Lu 2022 Figure 1 caption labels the unconjugated-DXd compartment with an apparent volumeV_DXd, but no numerical value appears in Table 3 (final), Table S7 (base), the main text, or the supplement. The released-payload ODEdA_DXd/dt = R_release - CLDXd * A_DXd / V_DXdrequiresV_DXdto resolve mass balance, so the model fixesV_DXd = 1 L(concentration-space normalisation). Operator-level guidance: this is documented as a deviation in the Assumptions and deviations section above; if a corrected value ofV_DXdis published in a future erratum or related-ADC paper (e.g., the cited Hong 2025 datopotamab deruxtecan model), updatevdxd <- 1.0in the model file accordingly. - Mixed time units between Tables 2 and 3. Lu 2022 Table 2 reports the antibody parameters in per-day units (CLlin in L/d, Vmax in ug/d) while Table 3 reports the unconjugated-DXd parameters in per-hour units (Krel in 1/h, CLDXd in L/h, beta in 1/h). The model converts the Table 3 rates and clearances to per-day by multiplying by 24 so the time variable is consistent throughout the joint ODE system. The conversion is a unit operation only and does not alter the source parameter values.
-
Vmaxmass-unit reporting. Lu 2022 Table 2 reportsVmax = 4352.2 ug/d. The model converts this to mg/d (4352.2 / 1000 = 4.3522 mg/d) so that the Michaelis-Menten elimination termVmax / (Km + C)is in L/d whenKmandCare in mg/L = ug/mL. The conversion preserves the source value exactly. -
Kmconcentration-unit reporting. Lu 2022 Table 2 reportsKm = 575.9 ng/mL. Converted to mg/L (575.9 / 1000 = 0.5759 mg/L = 0.5759 ug/mL) for unit consistency withVmax(mg/d) and the antibody concentration (mg/L = ug/mL). -
DXd-conjugated antibody additive residual error fixed at the
LLOQ. Lu 2022 Results note that the additive error ‘was fixed
to the LLOQ of 100 ng/mL, as it could not be estimated reliably (the
estimate was 606 ng/mL with a standard error > 3e9)’. The model
applies this fixing exactly via
CcaddSd <- fix(0.1)(in ug/mL). -
Unconjugated-DXd additive residual error fixed at
LLOQ. Lu 2022 Results note: ‘The additive error in the combined
residual error model was fixed to 0.01 ng/mL (the LLOQ for DXd), as the
estimation of the additive error was not reliable and led to the failure
of the covariance step’. The model applies this fixing exactly via
CdxdaddSd <- fix(0.01). -
Composite moderate-or-data-missing hepatic-function
indicator. Lu 2022 Table 3 row
Hepatic impairment moderate/data missing-CLDXd = 0.532pools the n = 6 NCI ODWG moderate-impairment patients with the n = 6 missing/unknown patients (Table S5) into a single coefficient because each subgroup is individually too small to estimate. The model captures this composite as a paper-specific canonicalHEPIMP_MOD_MISSINGindicator paired withHEPIMP_MILD. Lu 2022 Discussion explicitly flags the limitation: ‘the effect of moderate hepatic function was not estimated, as the relevant data were too limited (n = 6) for the evaluation to be reliable using the population PK approach.’