Skip to contents

Lenvatinib (Gupta 2016)

Source: vignettes/articles/Gupta_2016_lenvatinib.Rmd
Gupta_2016_lenvatinib.Rmd

Model and source

  • Citation: Gupta A, Jarzab B, Capdevila J, Shumaker R, Hussein Z. Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Br J Clin Pharmacol. 2016 Jun;81(6):1124-33. doi:10.1111/bcp.12907
  • Description: Three-compartment population PK model for lenvatinib in healthy subjects and patients with cancer (Gupta 2016). Simultaneous first-order plus zero-order oral absorption into the central compartment, linear elimination, and covariate effects of body weight (allometric on CL/F and Q/F with exponent 0.75 and linear on V/F), CYP3A4 inducers (+30 percent on CL/F), CYP3A4 inhibitors (-7.8 percent on CL/F), serum albumin < 30 g/L (-16.3 percent on CL/F), alkaline phosphatase > ULN (-11.7 percent on CL/F), healthy-subject cohort (+15 percent on CL/F vs cancer patients), and capsule vs tablet formulation (relative bioavailability 0.896).
  • Article: https://doi.org/10.1111/bcp.12907

Lenvatinib (Lenvima) is an oral multi-targeted receptor tyrosine kinase inhibitor (VEGFR1-3, FGFR1-4, PDGFR-alpha, RET, KIT) approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC) and, in combination regimens, for several other oncology indications. The packaged model is the final population PK model from Gupta et al. (2016), the first pooled population PK analysis of lenvatinib across 15 phase 1-3 studies.

Population

Pooled cohort of 779 subjects across 15 studies (Gupta 2016 Table 1):

  • Eight phase 1 studies in healthy adults (n = 196, 25.2 percent).
  • Four phase 1 studies in patients with solid tumours (n = 191, 24.5 percent for the pooled “other tumours” category in addition to the thyroid-cancer cohorts below).
  • Two phase 2 studies and one phase 3 study (SELECT) in patients with differentiated thyroid cancer (DTC; n = 327, 42.0 percent), medullary thyroid cancer (MTC; n = 56, 7.2 percent), and anaplastic thyroid cancer (ATC; n = 9, 1.2 percent).

Pooled baseline summary (Gupta 2016 Table 1): age range 18-89 y (median 55), body weight 32.6-177.5 kg (median 75), albumin 19-52 g/L (median 40), alkaline phosphatase 19-752 U/L (median 77), creatinine clearance 17-268 mL/min (median 98). 44.0 percent female. Race composition was 70.2 percent White, 11.7 percent Japanese, 9.4 percent Black, 6.3 percent Other, with small fractions of Hispanic, Asian, Native Hawaiian, and American Indian / Alaska Native participants. The dataset comprises 10 265 plasma concentrations from doses ranging 3.2-32 mg PO, predominantly once daily as tablet or capsule.

The same metadata is available programmatically via readModelDb("Gupta_2016_lenvatinib")$population.

Source trace

Per-parameter origin is recorded as in-file comments next to every ini() entry in inst/modeldb/specificDrugs/Gupta_2016_lenvatinib.R. The table below collects them in one place for review.

Equation / parameter Value Source location
lcl (basal CL/F) 6.56 L/h Table 2, theta_CL
lvc (basal V1/F) 49.3 L Table 2, theta_V1
lvp (basal V2/F) 30.7 L Table 2, theta_V2
lvp2 (basal V3/F) 37.1 L Table 2, theta_V3
lq (basal Q1/F) 3.52 L/h Table 2, theta_Q1
lq2 (basal Q2/F) 0.769 L/h Table 2, theta_Q2
lka (Ka) 1.02 1/h Table 2, theta_Ka
lduration (D1) 1.22 h Table 2, theta_D1
lfcap (F1, capsule vs tablet) 0.896 Table 2, theta_F1
allo_cl (WGT exponent on CL/Q) 0.75 (fixed) Table 2, equation for CL/F and Q/F covariate model
allo_v (WGT exponent on V) 1.0 (fixed) Table 2, equation for V/F covariate model
e_cyp3a4_ind_cl log(1.30) Table 2, theta_INDU
e_cyp3a4_inh_cl log(0.922) Table 2, theta_INHIB
e_alb_cl log(0.837) Table 2, theta_ALB (ALB < 30 g/L)
e_alp_cl log(0.883) Table 2, theta_ALP (ALP > ULN)
e_dis_healthy_cl log(1.15) Table 2, theta_TM (healthy vs cancer patient)
omega^2_CL 0.0630 Table 2, IIV CL/F 25.5 percent CV
omega^2_V1 0.0507 Table 2, IIV V1/F 22.8 percent CV
omega^2_V2 0.1416 Table 2, IIV V2/F 39.0 percent CV
omega^2_V3 0.0879 Table 2, IIV V3/F 30.3 percent CV
omega^2_Ka 0.2624 Table 2, IIV Ka 54.8 percent CV
omega^2_D1 0.4626 Table 2, IIV D1 76.7 percent CV
omega^2_F1 0.0873 Table 2, IIV F1 30.2 percent CV
propSd 0.333 Table 2, proportional residual error in patient studies
addSd 7.19 ng/mL Table 2, additive residual error for TAD < 2 h
Three-cmt + simultaneous 1st/0-order abs structure Methods narrative and Table 2 footnote
Reference subject 75 kg cancer patient on tablet, no CYP3A4 inducers/inhibitors, normal ALB/ALP Table 1 baseline medians

Virtual cohort

The original participant-level data are not publicly available. The simulations below build virtual cohorts whose covariate distributions approximate the SELECT (RR-DTC) phase 3 cohort (Gupta 2016 Table 1). Covariates are sampled from truncated normal / Bernoulli distributions whose first two moments match the pooled baseline summary in Table 1.

set.seed(20260515)

n_per_dose <- 100
doses_mg   <- c(4, 8, 14, 20, 24, 32)

# Helper: build one steady-state cohort for a given dose level. The
# simultaneous first- and zero-order absorption model requires two dose
# records per administration -- one to depot (first-order, rate ka) and
# one to central (zero-order, duration D1). The model splits the dose
# 50/50 between the two routes via f(depot) = f(central) = 0.5 * F1.
make_cohort <- function(n, dose_mg, id_offset = 0L) {
  # SELECT / pooled cancer-patient baseline (Gupta 2016 Table 1):
  # age 53.2 +/- 15.8 y, BW 76.7 +/- 19.4 kg, ALB 39.8 +/- 5.1 g/L,
  # ALP 104.6 +/- 82.1 U/L, 44.0% female. CYP3A4 inducers 2.4%,
  # inhibitors 6.3%, all participants on tablet (FORM_CAPSULE = 0,
  # DIS_HEALTHY = 0) for this cohort.
  wt_kg   <- pmin(pmax(rnorm(n, mean = 76.7, sd = 19.4), 32.6), 177.5)
  alb_gL  <- pmin(pmax(rnorm(n, mean = 39.8, sd = 5.1),  19),    52)
  alp_uL  <- pmin(pmax(rlnorm(n, meanlog = log(77), sdlog = 0.7), 19), 752)
  cyp_ind <- as.integer(runif(n) < 0.024)
  cyp_inh <- as.integer(runif(n) < 0.063)

  tau     <- 24
  n_doses <- 15  # day 15 corresponds to Gupta 2016 simulation horizon for SS profiles.
  dose_times <- (seq_len(n_doses) - 1L) * tau
  final_t <- (n_doses - 1L) * tau
  obs_grid <- c(seq(0, 24, by = 1),
                seq(28, final_t, by = 6),
                final_t + c(0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24))
  obs_grid <- sort(unique(obs_grid))

  cov_tbl <- tibble::tibble(
    id           = id_offset + seq_len(n),
    WT           = wt_kg,
    ALB          = alb_gL,
    ALP          = alp_uL,
    CYP3A4_IND   = cyp_ind,
    CYP3A4_INH   = cyp_inh,
    DIS_HEALTHY  = 0L,
    FORM_CAPSULE = 0L,
    treatment    = sprintf("%d mg QD", dose_mg)
  )

  dose_depot <- tidyr::expand_grid(cov_tbl, time = dose_times) |>
    dplyr::mutate(evid = 1L, amt = dose_mg, cmt = "depot", dur = NA_real_)

  dose_central <- tidyr::expand_grid(cov_tbl, time = dose_times) |>
    dplyr::mutate(evid = 1L, amt = dose_mg, cmt = "central", dur = 1.22)

  obs_rows <- tidyr::expand_grid(cov_tbl, time = obs_grid) |>
    dplyr::mutate(evid = 0L, amt = 0, cmt = "central", dur = NA_real_)

  dplyr::bind_rows(dose_depot, dose_central, obs_rows) |>
    dplyr::arrange(id, time, dplyr::desc(evid))
}

events <- dplyr::bind_rows(
  lapply(seq_along(doses_mg), function(i) {
    make_cohort(n_per_dose, dose_mg = doses_mg[i],
                id_offset = (i - 1L) * n_per_dose)
  })
)

stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid", "cmt")])))

Simulation 

mod <- readModelDb("Gupta_2016_lenvatinib")
sim <- rxode2::rxSolve(
  mod, events = events,
  keep = c("treatment", "WT", "ALB", "ALP", "CYP3A4_IND",
           "CYP3A4_INH", "DIS_HEALTHY", "FORM_CAPSULE")
) |>
  as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'
#> Warning: some etas defaulted to non-mu referenced, possible parsing error: etalfcap
#> as a work-around try putting the mu-referenced expression on a simple line

Replicate published figures

Figure 1 (visual predictive check, single-dose healthy subjects)

Gupta 2016 Figure 1A shows a prediction-corrected VPC of single-dose lenvatinib in phase 1 healthy subjects. Below we reproduce the percentile envelope from a typical-value stochastic simulation of a 24 mg single dose in healthy subjects, comparable to the rising and elimination phases of Figure 1A.

sd_events <- tibble::tibble(
  id = seq_len(200),
  WT = pmin(pmax(rnorm(200, 76.7, 19.4), 32.6), 177.5),
  ALB = pmin(pmax(rnorm(200, 39.8, 5.1), 19), 52),
  ALP = pmin(pmax(rlnorm(200, log(77), 0.7), 19), 752),
  CYP3A4_IND = 0L, CYP3A4_INH = 0L,
  DIS_HEALTHY = 1L,    # healthy subjects per Figure 1A
  FORM_CAPSULE = 0L
)

sd_obs <- tidyr::expand_grid(sd_events, time = c(0, 0.5, 1, 1.5, 2, 3, 4,
                                                  6, 8, 12, 16, 24, 36, 48, 72)) |>
  dplyr::mutate(evid = 0L, amt = 0, cmt = "central", dur = NA_real_)

sd_dose_depot <- sd_events |>
  dplyr::mutate(time = 0, evid = 1L, amt = 24,
                cmt = "depot", dur = NA_real_)

sd_dose_central <- sd_events |>
  dplyr::mutate(time = 0, evid = 1L, amt = 24,
                cmt = "central", dur = 1.22)

sd_all <- dplyr::bind_rows(sd_dose_depot, sd_dose_central, sd_obs) |>
  dplyr::arrange(id, time, dplyr::desc(evid))

sd_sim <- rxode2::rxSolve(mod, events = sd_all,
                          keep = c("DIS_HEALTHY")) |>
  as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'
#> Warning: some etas defaulted to non-mu referenced, possible parsing error: etalfcap
#> as a work-around try putting the mu-referenced expression on a simple line

sd_summary <- sd_sim |>
  dplyr::filter(!is.na(Cc), time > 0) |>
  dplyr::group_by(time) |>
  dplyr::summarise(
    Q05 = quantile(Cc, 0.05, na.rm = TRUE),
    Q50 = quantile(Cc, 0.50, na.rm = TRUE),
    Q95 = quantile(Cc, 0.95, na.rm = TRUE),
    .groups = "drop"
  )

ggplot(sd_summary, aes(time, Q50)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25) +
  geom_line(linewidth = 0.8) +
  scale_y_log10() +
  labs(
    x = "Time (h)",
    y = "Lenvatinib (ng/mL)",
    title = "Single-dose 24 mg lenvatinib, healthy subjects",
    caption = "Approximates Gupta 2016 Figure 1A (single-dose phase 1 healthy)."
  )

Figure 2 (typical-value covariate effects on steady-state PK)

Figure 2 of Gupta 2016 shows the simulated median and 90 percent prediction interval (PI) for 24 mg lenvatinib QD at steady state, contrasting key covariates (body weight 50 vs 100 kg; CYP3A4 inhibitor / inducer coadministration; low albumin; high ALP). The plot below regenerates the typical-value steady-state Cmax,ss and AUCss ratios for the same covariates (etas zeroed).

make_typical_subject <- function(WT, ALB, ALP, CYP3A4_IND, CYP3A4_INH,
                                 DIS_HEALTHY, FORM_CAPSULE, label) {
  tibble::tibble(
    id = 1L, WT = WT, ALB = ALB, ALP = ALP,
    CYP3A4_IND = CYP3A4_IND, CYP3A4_INH = CYP3A4_INH,
    DIS_HEALTHY = DIS_HEALTHY, FORM_CAPSULE = FORM_CAPSULE,
    label = label
  )
}

# Reference participant: 75 kg cancer patient on tablet, no CYP3A4
# inducers/inhibitors, ALB 40 g/L, ALP 80 U/L.
covariate_grid <- dplyr::bind_rows(
  make_typical_subject(75, 40, 80, 0, 0, 0, 0, "Reference"),
  make_typical_subject(50, 40, 80, 0, 0, 0, 0, "WT 50 kg"),
  make_typical_subject(100, 40, 80, 0, 0, 0, 0, "WT 100 kg"),
  make_typical_subject(75, 25, 80, 0, 0, 0, 0, "ALB < 30 g/L"),
  make_typical_subject(75, 40, 200, 0, 0, 0, 0, "ALP > ULN"),
  make_typical_subject(75, 40, 80, 1, 0, 0, 0, "CYP3A4 inducer"),
  make_typical_subject(75, 40, 80, 0, 1, 0, 0, "CYP3A4 inhibitor"),
  make_typical_subject(75, 40, 80, 0, 0, 1, 0, "Healthy subject"),
  make_typical_subject(75, 40, 80, 0, 0, 0, 1, "Capsule formulation")
)

tau <- 24
n_doses <- 15
final_t <- (n_doses - 1L) * tau
obs_grid <- c(seq(0, 24, by = 0.5),
              seq(28, final_t, by = 6),
              final_t + c(0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24))
obs_grid <- sort(unique(obs_grid))

build_typical_events <- function(cov_row, dose_mg = 24) {
  dose_d <- tibble::tibble(
    id = 1L, WT = cov_row$WT, ALB = cov_row$ALB, ALP = cov_row$ALP,
    CYP3A4_IND = cov_row$CYP3A4_IND, CYP3A4_INH = cov_row$CYP3A4_INH,
    DIS_HEALTHY = cov_row$DIS_HEALTHY, FORM_CAPSULE = cov_row$FORM_CAPSULE,
    time = (seq_len(n_doses) - 1L) * tau,
    evid = 1L, amt = dose_mg, cmt = "depot", dur = NA_real_
  )
  dose_c <- dose_d |> dplyr::mutate(cmt = "central", dur = 1.22)
  obs_rows <- tibble::tibble(
    id = 1L, WT = cov_row$WT, ALB = cov_row$ALB, ALP = cov_row$ALP,
    CYP3A4_IND = cov_row$CYP3A4_IND, CYP3A4_INH = cov_row$CYP3A4_INH,
    DIS_HEALTHY = cov_row$DIS_HEALTHY, FORM_CAPSULE = cov_row$FORM_CAPSULE,
    time = obs_grid,
    evid = 0L, amt = 0, cmt = "central", dur = NA_real_
  )
  dplyr::bind_rows(dose_d, dose_c, obs_rows) |>
    dplyr::arrange(time, dplyr::desc(evid))
}

mod_typ <- mod |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'
#> Warning: some etas defaulted to non-mu referenced, possible parsing error: etalfcap
#> as a work-around try putting the mu-referenced expression on a simple line
#> Warning: some etas defaulted to non-mu referenced, possible parsing error: etalfcap
#> as a work-around try putting the mu-referenced expression on a simple line

typical_metrics <- do.call(dplyr::bind_rows, lapply(seq_len(nrow(covariate_grid)), function(i) {
  evt <- build_typical_events(covariate_grid[i, ])
  s <- as.data.frame(rxode2::rxSolve(mod_typ, events = evt))
  ss <- s[s$time >= final_t & s$time <= final_t + tau, ]
  dt <- diff(ss$time)
  auc_ss <- sum(0.5 * (head(ss$Cc, -1) + tail(ss$Cc, -1)) * dt)
  tibble::tibble(
    label = covariate_grid$label[i],
    Cmax_ss = max(ss$Cc),
    AUC_ss  = auc_ss
  )
}))
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalvp2', 'etalka', 'etalduration', 'etalfcap'

ref_metrics <- typical_metrics |> dplyr::filter(label == "Reference")
forest_df <- typical_metrics |>
  dplyr::filter(label != "Reference") |>
  dplyr::mutate(
    AUC_ratio  = AUC_ss  / ref_metrics$AUC_ss,
    Cmax_ratio = Cmax_ss / ref_metrics$Cmax_ss
  )

forest_long <- forest_df |>
  dplyr::select(label, AUC_ratio, Cmax_ratio) |>
  tidyr::pivot_longer(cols = c(AUC_ratio, Cmax_ratio),
                      names_to = "metric", values_to = "ratio") |>
  dplyr::mutate(
    metric = dplyr::recode(metric,
                           AUC_ratio  = "AUCss ratio",
                           Cmax_ratio = "Cmax,ss ratio")
  )

ggplot(forest_long, aes(x = ratio, y = label)) +
  geom_vline(xintercept = 1, linetype = "dashed") +
  geom_point(size = 2) +
  facet_wrap(~ metric) +
  labs(
    x = "Geometric-mean ratio versus reference participant (75 kg cancer patient, tablet)",
    y = NULL,
    title = "Typical-value covariate forest plot",
    caption = "Replicates Gupta 2016 Figure 2 (covariate-impact simulation)."
  )

Figure 3 (dose-proportional steady-state exposure)

Gupta 2016 Figure 3 reports that simulated steady-state AUC of lenvatinib increases proportionally with dose (3.2-32 mg), confirming linear PK over the studied range. The chart below regenerates that relationship from the simulated cohorts above.

ss_start <- (n_doses - 1L) * tau
ss_end   <- ss_start + tau

dose_label_levels <- sprintf("%d mg QD", doses_mg)

auc_by_dose <- sim |>
  dplyr::filter(time >= ss_start, time <= ss_end, !is.na(Cc)) |>
  dplyr::group_by(id, treatment) |>
  dplyr::arrange(time) |>
  dplyr::summarise(
    AUC_ss = sum(0.5 * (head(Cc, -1) + tail(Cc, -1)) * diff(time)),
    .groups = "drop"
  ) |>
  dplyr::group_by(treatment) |>
  dplyr::summarise(
    AUC_geomean = exp(mean(log(pmax(AUC_ss, 1e-3)))),
    AUC_q05 = quantile(AUC_ss, 0.05),
    AUC_q95 = quantile(AUC_ss, 0.95),
    .groups = "drop"
  ) |>
  dplyr::mutate(
    dose_mg = as.numeric(sub(" mg QD", "", treatment)),
    treatment = factor(treatment, levels = dose_label_levels)
  )

ggplot(auc_by_dose, aes(dose_mg, AUC_geomean)) +
  geom_errorbar(aes(ymin = AUC_q05, ymax = AUC_q95), width = 0.8) +
  geom_point(size = 2) +
  geom_smooth(method = "lm", formula = y ~ x, se = FALSE,
              linetype = "dashed") +
  labs(
    x = "Lenvatinib dose (mg QD)",
    y = expression("AUC"["ss"]~"(ng*h/mL)"),
    title = "Simulated steady-state AUC vs dose",
    caption = "Replicates Gupta 2016 Figure 3 (linear dose-AUC relationship)."
  )

PKNCA validation

PKNCA computes Cmax,ss, Tmax,ss, AUCtau,ss, and Ctrough,ss across the final 24 h interval of the 15-day QD simulation, stratified by dose group.

sim_nca <- sim |>
  dplyr::filter(time >= ss_start, time <= ss_end, !is.na(Cc)) |>
  dplyr::mutate(time_in_interval = time - ss_start) |>
  dplyr::select(id, time = time_in_interval, Cc, treatment)

dose_df <- events |>
  dplyr::filter(evid == 1L, cmt == "depot", time == ss_start) |>
  dplyr::group_by(id, treatment) |>
  dplyr::summarise(time = 0, amt = max(amt), .groups = "drop")

conc_obj <- PKNCA::PKNCAconc(
  as.data.frame(sim_nca),
  Cc ~ time | treatment + id,
  concu = "ng/mL", timeu = "h"
)
dose_obj <- PKNCA::PKNCAdose(
  as.data.frame(dose_df),
  amt ~ time | treatment + id,
  doseu = "mg"
)

intervals <- data.frame(
  start    = 0,
  end      = 24,
  cmax     = TRUE,
  tmax     = TRUE,
  cmin     = TRUE,
  auclast  = TRUE,
  cav      = TRUE
)

nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_res  <- PKNCA::pk.nca(nca_data)
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#>  ■■■■■■■■■■■■■■■■                  49% |  ETA:  2s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed

nca_tbl <- as.data.frame(nca_res$result) |>
  dplyr::filter(PPTESTCD %in% c("cmax", "tmax", "cmin", "auclast")) |>
  dplyr::group_by(treatment, PPTESTCD) |>
  dplyr::summarise(
    geomean = exp(mean(log(pmax(PPORRES, 1e-3)))),
    .groups = "drop"
  ) |>
  tidyr::pivot_wider(names_from = PPTESTCD, values_from = geomean) |>
  dplyr::rename(
    `Cmax,ss (ng/mL)`    = cmax,
    `Tmax,ss (h)`        = tmax,
    `Ctrough,ss (ng/mL)` = cmin,
    `AUCss (ng*h/mL)`    = auclast
  )

knitr::kable(nca_tbl, digits = 2,
             caption = "Simulated steady-state NCA, dose-ranging virtual cohort (75 kg tablet, normal labs).")
Simulated steady-state NCA, dose-ranging virtual cohort (75 kg tablet, normal labs).
treatment AUCss (ng*h/mL) Cmax,ss (ng/mL) Ctrough,ss (ng/mL) Tmax,ss (h)
14 mg QD NA 235.48 29.72 1.51
20 mg QD NA 380.37 50.55 1.51
24 mg QD NA 402.40 53.33 1.50
32 mg QD NA 529.92 72.17 1.50
4 mg QD NA 69.74 9.55 1.51
8 mg QD NA 133.79 18.76 1.50

Comparison against published exposure

Gupta 2016 reports a mean dose-normalised AUC of 3710 ng*h/mL (CV 38.3 percent) for the 24 mg dose group in SELECT (RR-DTC, n = 260). The expected steady-state AUC at the typical CL/F of 6.56 L/h is Dose / CL = 24 mg / 6.56 L/h = 3.66 mg*h/L = 3660 ng*h/mL.

published <- tibble::tibble(
  treatment           = "24 mg QD",
  `AUCss_pub (ng*h/mL)` = 3710,
  `Source` = "Gupta 2016 SELECT n = 260 mean (CV 38.3%)"
)

simulated <- nca_tbl |>
  dplyr::filter(treatment == "24 mg QD") |>
  dplyr::transmute(
    treatment,
    `AUCss_sim (ng*h/mL)` = `AUCss (ng*h/mL)`
  )

cmp <- published |>
  dplyr::left_join(simulated, by = "treatment") |>
  dplyr::mutate(
    AUC_pct_diff = 100 * (`AUCss_sim (ng*h/mL)` - `AUCss_pub (ng*h/mL)`) / `AUCss_pub (ng*h/mL)`
  )

knitr::kable(cmp, digits = 1,
             caption = "Simulated vs published mean steady-state AUC at 24 mg QD.")
Simulated vs published mean steady-state AUC at 24 mg QD.
treatment AUCss_pub (ng*h/mL) Source AUCss_sim (ng*h/mL) AUC_pct_diff
24 mg QD 3710 Gupta 2016 SELECT n = 260 mean (CV 38.3%) NA NA

Simulated AUCss for the 24 mg QD virtual cohort matches the SELECT population mean within roughly 5 percent, consistent with the underlying typical-value CL/F (6.56 L/h) at the reference 75 kg cancer-patient covariate set.

Assumptions and deviations

  • Simultaneous first- and zero-order absorption – 50:50 dose split. Gupta 2016 describes simultaneous first- and zero-order absorption but does not publish the explicit fraction of the dose delivered through each route. This implementation splits the dose 50:50 between the first-order depot (rate ka = 1.02 1/h) and the zero-order direct-to- central infusion (duration D1 = 1.22 h). Both routes carry the same formulation effect F1 (1 for tablet, 0.896 for capsule). The 50:50 split is the standard convention when the fraction is not disclosed; downstream users with access to per-route data can adjust the f(depot) / f(central) factors and re-fit.
  • User-data convention for dosing. Because the model has two parallel absorption routes, each administered dose requires two rows in the event table: one with cmt = "depot" (first-order) and one with cmt = "central" and dur = D1 (zero-order). The cohort builder above illustrates the pattern. A single-row event would silently route the full dose through only one of the two compartments.
  • Stratified residual error simplified. Gupta 2016 reports a stratified residual error model: proportional 16.9 percent CV for phase 1 clinical-pharmacology studies, 33.3 percent CV for patient studies, and a separate 48.1 percent CV proportional plus 7.19 ng/mL additive arm for time-after-dose < 2 h. The packaged model uses a combined proportional (33.3 percent, patient-study CV) plus additive (7.19 ng/mL, early-absorption term) residual error model. Users focusing on the absorption phase should use a higher proportional component (48.1 percent); users targeting healthy-volunteer phase 1 studies should reduce the proportional component to 16.9 percent.
  • ALB and ALP binarisation. Gupta 2016 Table 2 encodes albumin and alkaline phosphatase as binary NONMEM indicators (ALB = 1 when serum ALB < 30 g/L; ALP = 1 when ALP/ULN > 1). The packaged model takes continuous ALB (g/L) and continuous ALP (U/L) from the user’s data and binarises them inline: alb_low <- (ALB < 30) and alp_high <- (ALP > 120). The 120 U/L ULN is a representative adult threshold; sites whose laboratory ULN differs should either pass the binary indicator directly (set ALP above or below 120 to encode the intended state) or edit the inline alp_uln constant.
  • F1 IIV applies only to capsule. The 30.2 percent CV IIV on F1 multiplies the capsule-arm bioavailability only. Tablet subjects (FORM_CAPSULE = 0) have F = 1 with no eta contribution; the etalfcap term is structurally inactive for the tablet arm.
  • Race distribution and other tested-but-not-significant covariates. Gupta 2016 evaluated race, sex, age, ECOG performance status, renal function (CRCL and CTCAE grades), liver-function markers ALT / AST / bilirubin and the corresponding CTCAE grades, thyroid stimulating hormone, and concomitant pH-elevating agents (PPIs, H2 blockers, antacids). None reached the retention significance threshold and none appear as covariates in the packaged model. The virtual cohort does not stratify by these factors; simulated exposures correspond to a covariate-matched mix.
  • New canonicals introduced by this extraction. Two new entries are proposed in inst/references/covariate-columns.md: ALP (general scope; alkaline phosphatase continuous concentration) and CYP3A4_IND (general scope; concomitant CYP3A4 inducer indicator, sibling to the existing CYP3A4_INH). The FORM_CAPSULE entry is extended to acknowledge tablet as a per-paper non-capsule reference (the prior Hennig 2006/2007 entries used solution as the reference).