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Midazolam preterm-neonate PBPK (Brussee 2018)

Source: vignettes/articles/Brussee_2018_midazolam_pbpk.Rmd
Brussee_2018_midazolam_pbpk.Rmd

Model and source

  • Citation: Brussee JM, Yu H, Krekels EHJ, de Roos B, Brill MJE, van den Anker JN, Rostami-Hodjegan A, de Wildt SN, Knibbe CAJ (2018). First-Pass CYP3A- Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT Pharmacometrics Syst Pharmacol 7(6):374-383. doi:10.1002/psp4.12295.
  • Description: PBPK (semi-physiological; well-stirred liver + Qgut gut wall) population PK model for midazolam and its primary metabolite 1-OH-midazolam in 37 preterm neonates (gestational age 26-34 weeks, body weight 0.770-2.030 kg at the time of dosing). Distinguishes first-pass CYP3A-mediated metabolism in the gut wall (Qgut model) and liver (well-stirred model) from systemic hepatic elimination of the metabolite. Tissue volumes (V_h, V_pv, V_gw) and hepatic blood flow Q_h are allometrically scaled from a term-neonate reference (Bjorkman 2005) by body weight with fixed exponents (1 for volumes, 0.75 for flow); intestinal length scales as 2.736 * WT[g]^0.512 cm (Struijs 2009) so the Qgut hybrid flow varies with body size. Supports oral administration (depot, full first-pass through gut wall and liver) and IV (dose directly to central; no first-pass).
  • Article: https://doi.org/10.1002/psp4.12295

Population

Brussee 2018 fit a semi-physiological population PK model to pooled IV and oral midazolam concentration data from 37 preterm neonates admitted to the neonatal intensive care unit of the Sophia’s Children Hospital (Rotterdam, NL). The cohort had gestational age at birth 26-34 weeks, birth weight 745-2,135 g, postnatal age 3-11 days, and body weight at the time of dosing 770-2,030 g. The source data combine de Wildt 2001 (IV cohort, Clin Pharmacol Ther 70:525-531) and de Wildt 2002 (oral cohort, Br J Clin Pharmacol 53:390-392): a 0.1 mg/kg dose given either orally via a nasogastric tube (n = 13) or as a 30-minute intravenous infusion (n = 25), with a crossover dose by the alternate route after >= 72 h in subjects still meeting inclusion criteria. Plasma midazolam and 1-OH-midazolam concentrations were collected at 0.5, 1, 2, 4, 6, 12, and 24 h post-dose; below-LLOQ samples (< 1% of 329 midazolam and < 2% of 153 1-OH-midazolam observations) were discarded before fitting. No covariates beyond body weight (which scales the physiological tissue volumes, blood flows, and intestinal-length terms) reached statistical significance in the covariate analysis.

The same information is available programmatically via readModelDb("Brussee_2018_midazolam_pbpk")$population.

Source trace

The per-parameter origin is recorded as an in-file comment next to every ini() entry in inst/modeldb/specificDrugs/Brussee_2018_midazolam_pbpk.R. The table below collects them in one place for review.

Equation / parameter Value Source location
Hepatic extraction E_h = (f_u,B * CL_int,H) / (f_u,B * CL_int,H + Q_h) derived Brussee 2018 Eq. 1
Gut wall extraction E_g = (f_u,G * CL_int,G) / (f_u,G * CL_int,G + Q_gut) derived Brussee 2018 Eq. 2
Qgut hybrid Q_gut = (Q_villi * CL_perm) / (Q_villi + CL_perm) derived Brussee 2018 Eq. 3
Intestinal surface A = 2*pi*radius*h, radius = 1 cm, h = 2.736 * WT[g]^0.512 cm derived Brussee 2018 Eq. 4 (Ives 2016, Struijs 2009)
Oral bioavailability F_total = F_a * F_g * F_h derived Brussee 2018 Eq. 5
Reference WT for term-neonate scaling 3.55 kg Bjorkman 2005 / Brussee 2018 Table 1
Reference liver volume V_h,3.55kg 0.120 L Brussee 2018 Table 1 (Bjorkman 2005 ref 7)
Portal vein / liver volume ratio 0.778 Brussee 2018 Table 1 (Aguirre-Reyes 2015 ref 24)
Reference gut wall volume V_gw,3.55kg 0.050 L Brussee 2018 Table 1
Reference hepatic blood flow Q_h,3.55kg 13.2 L/h Brussee 2018 Table 1
Blood-flow ratios (Q_pv, Q_ha, Q_in, Q_muc, Q_villi) 0.75, 0.25, 0.4, 0.8, 0.6 Brussee 2018 Table 1 (Johnson 2006, Yang 2007 refs 5, 25, 32)
Effective intestinal permeability P_eff,man (midazolam) 4.4e-4 cm/s = 1.584 cm/h Brussee 2018 Table 1 (Yang 2007 ref 25)
Midazolam unbound fraction in blood f_u,B 0.04094 Brussee 2018 Table 1 (McNamara-Alcorn from f_u,adult = 0.0303, [P]_pediatric = 27.1, [P]_adult = 37.0)
Midazolam unbound fraction in gut f_u,G 1 Brussee 2018 Methods (Yang 2007 ref 25)
Midazolam blood:plasma B:P 0.568 Brussee 2018 Table 1 (Maharaj 2013 ref 30)
1-OH-midazolam unbound in blood f_u,M 0.1394 Brussee 2018 Table 1 (from f_u,M,adult = 0.106, Mandema 1992 ref 29)
1-OH-midazolam blood:plasma B:P 0.613 Brussee 2018 Table 1
Fraction metabolised to 1-OH-midazolam f_M 1 Brussee 2018 Table 1
Absorption rate constant k_a 10 1/h (fixed) Brussee 2018 Methods (Table 1; sensitivity analysis 4.16-25 1/h)
Midazolam intrinsic hepatic CL CL_H,int 6.7 L/h (RSE 10%) Brussee 2018 Table 2
Midazolam intrinsic gut wall CL CL_G,int 0.0196 L/h (RSE 178%) Brussee 2018 Table 2
Midazolam apparent V (blood) 3.0 L (RSE 11%) Brussee 2018 Table 2
1-OH-midazolam intrinsic hepatic CL CL_H,int,M 8.9 L/h (RSE 22%) Brussee 2018 Table 2
1-OH-midazolam apparent V (blood) 2.7 L (RSE 43%) Brussee 2018 Table 2
IIV omega^2 (CL_H,int, V, CL_H,int,M, V_M) 0.887, 0.603, 0.832, 0.887 Brussee 2018 Table 2
Proportional residual error sigma^2 (parent / metabolite) 0.201 / 0.164 Brussee 2018 Table 2
Additive residual error sigma^2 (parent / metabolite) 0.0001 FIX (both) Brussee 2018 Table 2

Virtual cohort

Original observed concentrations from de Wildt 2001/2002 are not openly available. The figures below use a 200-subject virtual cohort whose body-weight distribution approximates the published trial demographics: a uniform sample from 0.77-2.03 kg (the body-weight range at the time of dosing reported in Methods Data).

set.seed(20180510)  # paper's published-online date

n_sub <- 200L
wt_range <- c(0.77, 2.03)  # kg

cohort_wt <- tibble::tibble(
  id = seq_len(n_sub),
  WT = runif(n_sub, min = wt_range[1], max = wt_range[2])
)

# Observation grid. Brussee 2018 Methods sampled at 0.5, 1, 2, 4, 6, 12, 24 h;
# use a denser grid here for smoother concentration-time profiles.
obs_times <- c(0.01, seq(0.25, 24, by = 0.25))

make_events <- function(cohort, route, dose_per_kg = 0.1, infusion_h = 0.5) {
  doses <- cohort |>
    dplyr::mutate(
      EVID = 1L,
      AMT  = dose_per_kg * WT * 1000,         # mg/kg * kg * 1000 = ug
      TIME = 0,
      CMT  = ifelse(route == "oral", "depot", "central"),
      RATE = ifelse(route == "iv30",
                    dose_per_kg * WT * 1000 / infusion_h,
                    NA_real_),
      route = route
    ) |>
    dplyr::select(id, EVID, AMT, RATE, TIME, CMT, WT, route)

  obs <- tidyr::expand_grid(
    cohort,
    TIME = obs_times
  ) |>
    dplyr::mutate(EVID = 0L, AMT = 0, RATE = NA_real_,
                  CMT = "Cc", route = route) |>
    dplyr::select(id, EVID, AMT, RATE, TIME, CMT, WT, route)

  dplyr::bind_rows(doses, obs) |>
    dplyr::arrange(id, TIME, dplyr::desc(EVID))
}

events_oral <- make_events(cohort_wt, "oral")
events_iv   <- make_events(cohort_wt, "iv30")

Simulation 

mod <- readModelDb("Brussee_2018_midazolam_pbpk")

sim_oral <- rxode2::rxSolve(
  mod, events = events_oral,
  keep = c("route", "WT"),
  returnType = "data.frame"
) |>
  dplyr::mutate(route = "Oral")
#> ℹ parameter labels from comments will be replaced by 'label()'

sim_iv <- rxode2::rxSolve(
  mod, events = events_iv,
  keep = c("route", "WT"),
  returnType = "data.frame"
) |>
  dplyr::mutate(route = "IV 30-min infusion")
#> ℹ parameter labels from comments will be replaced by 'label()'

sim <- dplyr::bind_rows(sim_oral, sim_iv)

The typical-value (population-mean) profile, useful for Figure 4 replication, zeros out the between-subject variability:

mod_typical <- mod |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'

# Typical 1.1 kg neonate
typical_cohort <- tibble::tibble(id = 1L, WT = 1.1)
typical_oral <- rxode2::rxSolve(
  mod_typical, events = make_events(typical_cohort, "oral"),
  keep = c("route", "WT"),
  returnType = "data.frame"
) |> dplyr::mutate(route = "Oral")
#> ℹ omega/sigma items treated as zero: 'etalcl_int_h', 'etalvc', 'etalcl_int_h_1ohm', 'etalvc_1ohm'
typical_iv <- rxode2::rxSolve(
  mod_typical, events = make_events(typical_cohort, "iv30"),
  keep = c("route", "WT"),
  returnType = "data.frame"
) |> dplyr::mutate(route = "IV 30-min infusion")
#> ℹ omega/sigma items treated as zero: 'etalcl_int_h', 'etalvc', 'etalcl_int_h_1ohm', 'etalvc_1ohm'

typical <- dplyr::bind_rows(typical_oral, typical_iv)

Replicate published figures

Figure 4a – Midazolam plasma profile (oral vs IV)

Brussee 2018 Figure 4a shows model-based simulations of midazolam plasma concentrations following a 0.1 mg/kg dose given orally (black) or as a 30-min infusion (gray) in the 37 preterm neonates from the study, with the median and minimal / maximal envelope.

sim |>
  dplyr::filter(time > 0) |>
  dplyr::group_by(route, 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(aes(time, Q50, colour = route, fill = route)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.15, colour = NA) +
  geom_line(linewidth = 0.8) +
  scale_y_log10() +
  labs(
    x = "Time after dose (hours)",
    y = "Midazolam plasma concentration (ng/mL)",
    colour = NULL, fill = NULL,
    title = "Figure 4a -- midazolam, oral vs IV 30-min infusion",
    caption = "Median with 5th-95th percentile band, 200-subject virtual cohort (WT 0.77-2.03 kg)."
  )
Replicates Figure 4a of Brussee 2018.

Replicates Figure 4a of Brussee 2018.

Figure 4b – 1-OH-midazolam plasma profile (oral vs IV)

Brussee 2018 Figure 4b shows the same simulation for the 1-OH-midazolam metabolite, where the oral curve climbs higher than the IV curve over the first 4 h because of presystemic conversion in the gut wall and liver.

sim |>
  dplyr::filter(time > 0) |>
  dplyr::group_by(route, time) |>
  dplyr::summarise(
    Q05 = quantile(Cc_1ohm, 0.05, na.rm = TRUE),
    Q50 = quantile(Cc_1ohm, 0.50, na.rm = TRUE),
    Q95 = quantile(Cc_1ohm, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  ggplot(aes(time, Q50, colour = route, fill = route)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.15, colour = NA) +
  geom_line(linewidth = 0.8) +
  scale_y_log10() +
  labs(
    x = "Time after dose (hours)",
    y = "1-OH-midazolam plasma concentration (ng/mL)",
    colour = NULL, fill = NULL,
    title = "Figure 4b -- 1-OH-midazolam, oral vs IV 30-min infusion",
    caption = "Median with 5th-95th percentile band; presystemic metabolism elevates the oral curve over 0-4 h."
  )
Replicates Figure 4b of Brussee 2018.

Replicates Figure 4b of Brussee 2018.

Figure 2 / 3 – extraction ratios and bioavailability vs body weight

Brussee 2018 Figures 2c and 3 report extraction ratios and bioavailability as scatter plots of typical-value model predictions across body weight. The extraction-ratio and bioavailability terms are computed inside model() and are exposed as derived outputs by rxSolve(), so the relationship across the cohort can be reproduced directly.

typical_grid <- tibble::tibble(
  id = seq_len(50),
  WT = seq(min(wt_range), max(wt_range), length.out = 50)
)
typical_grid_oral <- rxode2::rxSolve(
  mod_typical, events = make_events(typical_grid, "oral"),
  keep = c("route", "WT"),
  returnType = "data.frame"
)
#> ℹ omega/sigma items treated as zero: 'etalcl_int_h', 'etalvc', 'etalcl_int_h_1ohm', 'etalvc_1ohm'
#> Warning: multi-subject simulation without without 'omega'
# Static extractions are time-invariant; pick the first observation row per ID
extractions <- typical_grid_oral |>
  dplyr::filter(time == min(time[time > 0])) |>
  dplyr::select(id, WT, eg, eh, eh_1ohm, fg, fh) |>
  dplyr::mutate(
    ftotal = fg * fh                       # F_a = 1
  )

extractions |>
  tidyr::pivot_longer(c(eg, eh, eh_1ohm, fg, fh, ftotal),
                      names_to = "quantity", values_to = "value") |>
  dplyr::mutate(panel = dplyr::case_when(
    quantity %in% c("eg", "eh", "eh_1ohm") ~ "Extraction ratios",
    TRUE                                   ~ "Bioavailability"
  )) |>
  ggplot(aes(WT, value, colour = quantity)) +
  geom_line() +
  geom_point(size = 1.2) +
  facet_wrap(~ panel, scales = "free_y") +
  labs(
    x = "Body weight (kg)",
    y = "Extraction ratio / bioavailability",
    colour = NULL,
    title = "Figures 2c & 3 -- extraction ratios and bioavailability vs WT",
    caption = "Typical-value, 50-point WT grid spanning 0.77-2.03 kg."
  )
Replicates Figures 2c and 3 of Brussee 2018: extraction ratio and bioavailability vs body weight.

Replicates Figures 2c and 3 of Brussee 2018: extraction ratio and bioavailability vs body weight.

PKNCA validation

Compute Cmax, Tmax, AUC, and apparent half-life for both routes via PKNCA and compare against the paper’s reported summary statistics.

sim_nca <- sim |>
  dplyr::filter(!is.na(Cc)) |>
  dplyr::transmute(id, time, Cc, treatment = route)

conc_obj <- PKNCA::PKNCAconc(sim_nca, Cc ~ time | treatment + id)
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found

dose_df <- dplyr::bind_rows(events_oral, events_iv) |>
  dplyr::filter(EVID == 1L) |>
  dplyr::transmute(id, time = TIME, amt = AMT, treatment = route)

dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | treatment + id)

intervals <- data.frame(
  start = 0, end = 24,
  cmax = TRUE, tmax = TRUE,
  auclast = TRUE, aucinf.obs = TRUE,
  half.life = TRUE
)

nca <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement
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#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.01) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.01) is not allowed
#> Warning: treatment=iv30; id=1: No concentration data
#> Warning: treatment=iv30; id=2: No concentration data
#> Warning: treatment=iv30; id=3: No concentration data
#> Warning: treatment=iv30; id=4: No concentration data
#> Warning: treatment=iv30; id=5: No concentration data
#> Warning: treatment=iv30; id=6: No concentration data
#> Warning: treatment=iv30; id=7: No concentration data
#> Warning: treatment=iv30; id=8: No concentration data
#> Warning: treatment=iv30; id=9: No concentration data
#> Warning: treatment=iv30; id=10: No concentration data
#> Warning: treatment=iv30; id=11: No concentration data
#> Warning: treatment=iv30; id=12: No concentration data
#> Warning: treatment=iv30; id=13: No concentration data
#> Warning: treatment=iv30; id=14: No concentration data
#> Warning: treatment=iv30; id=15: No concentration data
#> Warning: treatment=iv30; id=16: No concentration data
#> Warning: treatment=iv30; id=17: No concentration data
#> Warning: treatment=iv30; id=18: No concentration data
#> Warning: treatment=iv30; id=19: No concentration data
#> Warning: treatment=iv30; id=20: No concentration data
#> Warning: treatment=iv30; id=21: No concentration data
#> Warning: treatment=iv30; id=22: No concentration data
#> Warning: treatment=iv30; id=23: No concentration data
#> Warning: treatment=iv30; id=24: No concentration data
#> Warning: treatment=iv30; id=25: No concentration data
#> Warning: treatment=iv30; id=26: No concentration data
#> Warning: treatment=iv30; id=27: No concentration data
#> Warning: treatment=iv30; id=28: No concentration data
#> Warning: treatment=iv30; id=29: No concentration data
#> Warning: treatment=iv30; id=30: No concentration data
#> Warning: treatment=iv30; id=31: No concentration data
#> Warning: treatment=iv30; id=32: No concentration data
#> Warning: treatment=iv30; id=33: No concentration data
#> Warning: treatment=iv30; id=34: No concentration data
#> Warning: treatment=iv30; id=35: No concentration data
#> Warning: treatment=iv30; id=36: No concentration data
#> Warning: treatment=iv30; id=37: No concentration data
#> Warning: treatment=iv30; id=38: No concentration data
#> Warning: treatment=iv30; id=39: No concentration data
#> Warning: treatment=iv30; id=40: No concentration data
#> Warning: treatment=iv30; id=41: No concentration data
#> Warning: treatment=iv30; id=42: No concentration data
#> Warning: treatment=iv30; id=43: No concentration data
#> Warning: treatment=iv30; id=44: No concentration data
#> Warning: treatment=iv30; id=45: No concentration data
#> Warning: treatment=iv30; id=46: No concentration data
#> Warning: treatment=iv30; id=47: No concentration data
#> Warning: treatment=iv30; id=48: No concentration data
#> Warning: treatment=iv30; id=49: No concentration data
#> Warning: treatment=iv30; id=50: No concentration data
#> Warning: treatment=iv30; id=51: No concentration data
#> Warning: treatment=iv30; id=52: No concentration data
#> Warning: treatment=iv30; id=53: No concentration data
#> Warning: treatment=iv30; id=54: No concentration data
#> Warning: treatment=iv30; id=55: No concentration data
#> Warning: treatment=iv30; id=56: No concentration data
#> Warning: treatment=iv30; id=57: No concentration data
#> Warning: treatment=iv30; id=58: No concentration data
#> Warning: treatment=iv30; id=59: No concentration data
#> Warning: treatment=iv30; id=60: No concentration data
#> Warning: treatment=iv30; id=61: No concentration data
#> Warning: treatment=iv30; id=62: No concentration data
#> Warning: treatment=iv30; id=63: No concentration data
#> Warning: treatment=iv30; id=64: No concentration data
#> Warning: treatment=iv30; id=65: No concentration data
#> Warning: treatment=iv30; id=66: No concentration data
#> Warning: treatment=iv30; id=67: No concentration data
#> Warning: treatment=iv30; id=68: No concentration data
#> Warning: treatment=iv30; id=69: No concentration data
#> Warning: treatment=iv30; id=70: No concentration data
#> Warning: treatment=iv30; id=71: No concentration data
#> Warning: treatment=iv30; id=72: No concentration data
#> Warning: treatment=iv30; id=73: No concentration data
#> Warning: treatment=iv30; id=74: No concentration data
#> Warning: treatment=iv30; id=75: No concentration data
#> Warning: treatment=iv30; id=76: No concentration data
#> Warning: treatment=iv30; id=77: No concentration data
#> Warning: treatment=iv30; id=78: No concentration data
#> Warning: treatment=iv30; id=79: No concentration data
#> Warning: treatment=iv30; id=80: No concentration data
#> Warning: treatment=iv30; id=81: No concentration data
#> Warning: treatment=iv30; id=82: No concentration data
#> Warning: treatment=iv30; id=83: No concentration data
#> Warning: treatment=iv30; id=84: No concentration data
#> Warning: treatment=iv30; id=85: No concentration data
#> Warning: treatment=iv30; id=86: No concentration data
#> Warning: treatment=iv30; id=87: No concentration data
#> Warning: treatment=iv30; id=88: No concentration data
#> Warning: treatment=iv30; id=89: No concentration data
#> Warning: treatment=iv30; id=90: No concentration data
#> Warning: treatment=iv30; id=91: No concentration data
#> Warning: treatment=iv30; id=92: No concentration data
#> Warning: treatment=iv30; id=93: No concentration data
#> Warning: treatment=iv30; id=94: No concentration data
#> Warning: treatment=iv30; id=95: No concentration data
#> Warning: treatment=iv30; id=96: No concentration data
#> Warning: treatment=iv30; id=97: No concentration data
#> Warning: treatment=iv30; id=98: No concentration data
#> Warning: treatment=iv30; id=99: No concentration data
#> Warning: treatment=iv30; id=100: No concentration data
#> Warning: treatment=iv30; id=101: No concentration data
#> Warning: treatment=iv30; id=102: No concentration data
#> Warning: treatment=iv30; id=103: No concentration data
#> Warning: treatment=iv30; id=104: No concentration data
#> Warning: treatment=iv30; id=105: No concentration data
#> Warning: treatment=iv30; id=106: No concentration data
#> Warning: treatment=iv30; id=107: No concentration data
#> Warning: treatment=iv30; id=108: No concentration data
#> Warning: treatment=iv30; id=109: No concentration data
#> Warning: treatment=iv30; id=110: No concentration data
#> Warning: treatment=iv30; id=111: No concentration data
#> Warning: treatment=iv30; id=112: No concentration data
#> Warning: treatment=iv30; id=113: No concentration data
#> Warning: treatment=iv30; id=114: No concentration data
#> Warning: treatment=iv30; id=115: No concentration data
#> Warning: treatment=iv30; id=116: No concentration data
#> Warning: treatment=iv30; id=117: No concentration data
#> Warning: treatment=iv30; id=118: No concentration data
#> Warning: treatment=iv30; id=119: No concentration data
#> Warning: treatment=iv30; id=120: No concentration data
#> Warning: treatment=iv30; id=121: No concentration data
#> Warning: treatment=iv30; id=122: No concentration data
#> Warning: treatment=iv30; id=123: No concentration data
#> Warning: treatment=iv30; id=124: No concentration data
#> Warning: treatment=iv30; id=125: No concentration data
#> Warning: treatment=iv30; id=126: No concentration data
#> Warning: treatment=iv30; id=127: No concentration data
#> Warning: treatment=iv30; id=128: No concentration data
#> Warning: treatment=iv30; id=129: No concentration data
#> Warning: treatment=iv30; id=130: No concentration data
#> Warning: treatment=iv30; id=131: No concentration data
#> Warning: treatment=iv30; id=132: No concentration data
#> Warning: treatment=iv30; id=133: No concentration data
#> Warning: treatment=iv30; id=134: No concentration data
#> Warning: treatment=iv30; id=135: No concentration data
#> Warning: treatment=iv30; id=136: No concentration data
#> Warning: treatment=iv30; id=137: No concentration data
#> Warning: treatment=iv30; id=138: No concentration data
#> Warning: treatment=iv30; id=139: No concentration data
#> Warning: treatment=iv30; id=140: No concentration data
#> Warning: treatment=iv30; id=141: No concentration data
#> Warning: treatment=iv30; id=142: No concentration data
#> Warning: treatment=iv30; id=143: No concentration data
#> Warning: treatment=iv30; id=144: No concentration data
#> Warning: treatment=iv30; id=145: No concentration data
#> Warning: treatment=iv30; id=146: No concentration data
#> Warning: treatment=iv30; id=147: No concentration data
#> Warning: treatment=iv30; id=148: No concentration data
#> Warning: treatment=iv30; id=149: No concentration data
#> Warning: treatment=iv30; id=150: No concentration data
#> Warning: treatment=iv30; id=151: No concentration data
#> Warning: treatment=iv30; id=152: No concentration data
#> Warning: treatment=iv30; id=153: No concentration data
#> Warning: treatment=iv30; id=154: No concentration data
#> Warning: treatment=iv30; id=155: No concentration data
#> Warning: treatment=iv30; id=156: No concentration data
#> Warning: treatment=iv30; id=157: No concentration data
#> Warning: treatment=iv30; id=158: No concentration data
#> Warning: treatment=iv30; id=159: No concentration data
#> Warning: treatment=iv30; id=160: No concentration data
#> Warning: treatment=iv30; id=161: No concentration data
#> Warning: treatment=iv30; id=162: No concentration data
#> Warning: treatment=iv30; id=163: No concentration data
#> Warning: treatment=iv30; id=164: No concentration data
#> Warning: treatment=iv30; id=165: No concentration data
#> Warning: treatment=iv30; id=166: No concentration data
#> Warning: treatment=iv30; id=167: No concentration data
#> Warning: treatment=iv30; id=168: No concentration data
#> Warning: treatment=iv30; id=169: No concentration data
#> Warning: treatment=iv30; id=170: No concentration data
#> Warning: treatment=iv30; id=171: No concentration data
#> Warning: treatment=iv30; id=172: No concentration data
#> Warning: treatment=iv30; id=173: No concentration data
#> Warning: treatment=iv30; id=174: No concentration data
#> Warning: treatment=iv30; id=175: No concentration data
#> Warning: treatment=iv30; id=176: No concentration data
#> Warning: treatment=iv30; id=177: No concentration data
#> Warning: treatment=iv30; id=178: No concentration data
#> Warning: treatment=iv30; id=179: No concentration data
#> Warning: treatment=iv30; id=180: No concentration data
#> Warning: treatment=iv30; id=181: No concentration data
#> Warning: treatment=iv30; id=182: No concentration data
#> Warning: treatment=iv30; id=183: No concentration data
#> Warning: treatment=iv30; id=184: No concentration data
#> Warning: treatment=iv30; id=185: No concentration data
#> Warning: treatment=iv30; id=186: No concentration data
#> Warning: treatment=iv30; id=187: No concentration data
#> Warning: treatment=iv30; id=188: No concentration data
#> Warning: treatment=iv30; id=189: No concentration data
#> Warning: treatment=iv30; id=190: No concentration data
#> Warning: treatment=iv30; id=191: No concentration data
#> Warning: treatment=iv30; id=192: No concentration data
#> Warning: treatment=iv30; id=193: No concentration data
#> Warning: treatment=iv30; id=194: No concentration data
#> Warning: treatment=iv30; id=195: No concentration data
#> Warning: treatment=iv30; id=196: No concentration data
#> Warning: treatment=iv30; id=197: No concentration data
#> Warning: treatment=iv30; id=198: No concentration data
#> Warning: treatment=iv30; id=199: No concentration data
#> Warning: treatment=iv30; id=200: No concentration data
#> Warning: treatment=oral; id=1: No concentration data
#> Warning: treatment=oral; id=2: No concentration data
#> Warning: treatment=oral; id=3: No concentration data
#> Warning: treatment=oral; id=4: No concentration data
#> Warning: treatment=oral; id=5: No concentration data
#> Warning: treatment=oral; id=6: No concentration data
#> Warning: treatment=oral; id=7: No concentration data
#> Warning: treatment=oral; id=8: No concentration data
#> Warning: treatment=oral; id=9: No concentration data
#> Warning: treatment=oral; id=10: No concentration data
#> Warning: treatment=oral; id=11: No concentration data
#> Warning: treatment=oral; id=12: No concentration data
#> Warning: treatment=oral; id=13: No concentration data
#> Warning: treatment=oral; id=14: No concentration data
#> Warning: treatment=oral; id=15: No concentration data
#> Warning: treatment=oral; id=16: No concentration data
#> Warning: treatment=oral; id=17: No concentration data
#> Warning: treatment=oral; id=18: No concentration data
#> Warning: treatment=oral; id=19: No concentration data
#> Warning: treatment=oral; id=20: No concentration data
#> Warning: treatment=oral; id=21: No concentration data
#> Warning: treatment=oral; id=22: No concentration data
#> Warning: treatment=oral; id=23: No concentration data
#> Warning: treatment=oral; id=24: No concentration data
#> Warning: treatment=oral; id=25: No concentration data
#> Warning: treatment=oral; id=26: No concentration data
#> Warning: treatment=oral; id=27: No concentration data
#> Warning: treatment=oral; id=28: No concentration data
#> Warning: treatment=oral; id=29: No concentration data
#> Warning: treatment=oral; id=30: No concentration data
#> Warning: treatment=oral; id=31: No concentration data
#> Warning: treatment=oral; id=32: No concentration data
#> Warning: treatment=oral; id=33: No concentration data
#> Warning: treatment=oral; id=34: No concentration data
#> Warning: treatment=oral; id=35: No concentration data
#> Warning: treatment=oral; id=36: No concentration data
#> Warning: treatment=oral; id=37: No concentration data
#> Warning: treatment=oral; id=38: No concentration data
#> Warning: treatment=oral; id=39: No concentration data
#> Warning: treatment=oral; id=40: No concentration data
#> Warning: treatment=oral; id=41: No concentration data
#> Warning: treatment=oral; id=42: No concentration data
#> Warning: treatment=oral; id=43: No concentration data
#> Warning: treatment=oral; id=44: No concentration data
#> Warning: treatment=oral; id=45: No concentration data
#> Warning: treatment=oral; id=46: No concentration data
#> Warning: treatment=oral; id=47: No concentration data
#> Warning: treatment=oral; id=48: No concentration data
#> Warning: treatment=oral; id=49: No concentration data
#> Warning: treatment=oral; id=50: No concentration data
#> Warning: treatment=oral; id=51: No concentration data
#> Warning: treatment=oral; id=52: No concentration data
#> Warning: treatment=oral; id=53: No concentration data
#> Warning: treatment=oral; id=54: No concentration data
#> Warning: treatment=oral; id=55: No concentration data
#> Warning: treatment=oral; id=56: No concentration data
#> Warning: treatment=oral; id=57: No concentration data
#> Warning: treatment=oral; id=58: No concentration data
#> Warning: treatment=oral; id=59: No concentration data
#> Warning: treatment=oral; id=60: No concentration data
#> Warning: treatment=oral; id=61: No concentration data
#> Warning: treatment=oral; id=62: No concentration data
#> Warning: treatment=oral; id=63: No concentration data
#> Warning: treatment=oral; id=64: No concentration data
#> Warning: treatment=oral; id=65: No concentration data
#> Warning: treatment=oral; id=66: No concentration data
#> Warning: treatment=oral; id=67: No concentration data
#> Warning: treatment=oral; id=68: No concentration data
#> Warning: treatment=oral; id=69: No concentration data
#> Warning: treatment=oral; id=70: No concentration data
#> Warning: treatment=oral; id=71: No concentration data
#> Warning: treatment=oral; id=72: No concentration data
#> Warning: treatment=oral; id=73: No concentration data
#> Warning: treatment=oral; id=74: No concentration data
#> Warning: treatment=oral; id=75: No concentration data
#> Warning: treatment=oral; id=76: No concentration data
#> Warning: treatment=oral; id=77: No concentration data
#> Warning: treatment=oral; id=78: No concentration data
#> Warning: treatment=oral; id=79: No concentration data
#> Warning: treatment=oral; id=80: No concentration data
#> Warning: treatment=oral; id=81: No concentration data
#> Warning: treatment=oral; id=82: No concentration data
#> Warning: treatment=oral; id=83: No concentration data
#> Warning: treatment=oral; id=84: No concentration data
#> Warning: treatment=oral; id=85: No concentration data
#> Warning: treatment=oral; id=86: No concentration data
#> Warning: treatment=oral; id=87: No concentration data
#> Warning: treatment=oral; id=88: No concentration data
#> Warning: treatment=oral; id=89: No concentration data
#> Warning: treatment=oral; id=90: No concentration data
#> Warning: treatment=oral; id=91: No concentration data
#> Warning: treatment=oral; id=92: No concentration data
#> Warning: treatment=oral; id=93: No concentration data
#> Warning: treatment=oral; id=94: No concentration data
#> Warning: treatment=oral; id=95: No concentration data
#> Warning: treatment=oral; id=96: No concentration data
#> Warning: treatment=oral; id=97: No concentration data
#> Warning: treatment=oral; id=98: No concentration data
#> Warning: treatment=oral; id=99: No concentration data
#> Warning: treatment=oral; id=100: No concentration data
#> Warning: treatment=oral; id=101: No concentration data
#> Warning: treatment=oral; id=102: No concentration data
#> Warning: treatment=oral; id=103: No concentration data
#> Warning: treatment=oral; id=104: No concentration data
#> Warning: treatment=oral; id=105: No concentration data
#> Warning: treatment=oral; id=106: No concentration data
#> Warning: treatment=oral; id=107: No concentration data
#> Warning: treatment=oral; id=108: No concentration data
#> Warning: treatment=oral; id=109: No concentration data
#> Warning: treatment=oral; id=110: No concentration data
#> Warning: treatment=oral; id=111: No concentration data
#> Warning: treatment=oral; id=112: No concentration data
#> Warning: treatment=oral; id=113: No concentration data
#> Warning: treatment=oral; id=114: No concentration data
#> Warning: treatment=oral; id=115: No concentration data
#> Warning: treatment=oral; id=116: No concentration data
#> Warning: treatment=oral; id=117: No concentration data
#> Warning: treatment=oral; id=118: No concentration data
#> Warning: treatment=oral; id=119: No concentration data
#> Warning: treatment=oral; id=120: No concentration data
#> Warning: treatment=oral; id=121: No concentration data
#> Warning: treatment=oral; id=122: No concentration data
#> Warning: treatment=oral; id=123: No concentration data
#> Warning: treatment=oral; id=124: No concentration data
#> Warning: treatment=oral; id=125: No concentration data
#> Warning: treatment=oral; id=126: No concentration data
#> Warning: treatment=oral; id=127: No concentration data
#> Warning: treatment=oral; id=128: No concentration data
#> Warning: treatment=oral; id=129: No concentration data
#> Warning: treatment=oral; id=130: No concentration data
#> Warning: treatment=oral; id=131: No concentration data
#> Warning: treatment=oral; id=132: No concentration data
#> Warning: treatment=oral; id=133: No concentration data
#> Warning: treatment=oral; id=134: No concentration data
#> Warning: treatment=oral; id=135: No concentration data
#> Warning: treatment=oral; id=136: No concentration data
#> Warning: treatment=oral; id=137: No concentration data
#> Warning: treatment=oral; id=138: No concentration data
#> Warning: treatment=oral; id=139: No concentration data
#> Warning: treatment=oral; id=140: No concentration data
#> Warning: treatment=oral; id=141: No concentration data
#> Warning: treatment=oral; id=142: No concentration data
#> Warning: treatment=oral; id=143: No concentration data
#> Warning: treatment=oral; id=144: No concentration data
#> Warning: treatment=oral; id=145: No concentration data
#> Warning: treatment=oral; id=146: No concentration data
#> Warning: treatment=oral; id=147: No concentration data
#> Warning: treatment=oral; id=148: No concentration data
#> Warning: treatment=oral; id=149: No concentration data
#> Warning: treatment=oral; id=150: No concentration data
#> Warning: treatment=oral; id=151: No concentration data
#> Warning: treatment=oral; id=152: No concentration data
#> Warning: treatment=oral; id=153: No concentration data
#> Warning: treatment=oral; id=154: No concentration data
#> Warning: treatment=oral; id=155: No concentration data
#> Warning: treatment=oral; id=156: No concentration data
#> Warning: treatment=oral; id=157: No concentration data
#> Warning: treatment=oral; id=158: No concentration data
#> Warning: treatment=oral; id=159: No concentration data
#> Warning: treatment=oral; id=160: No concentration data
#> Warning: treatment=oral; id=161: No concentration data
#> Warning: treatment=oral; id=162: No concentration data
#> Warning: treatment=oral; id=163: No concentration data
#> Warning: treatment=oral; id=164: No concentration data
#> Warning: treatment=oral; id=165: No concentration data
#> Warning: treatment=oral; id=166: No concentration data
#> Warning: treatment=oral; id=167: No concentration data
#> Warning: treatment=oral; id=168: No concentration data
#> Warning: treatment=oral; id=169: No concentration data
#> Warning: treatment=oral; id=170: No concentration data
#> Warning: treatment=oral; id=171: No concentration data
#> Warning: treatment=oral; id=172: No concentration data
#> Warning: treatment=oral; id=173: No concentration data
#> Warning: treatment=oral; id=174: No concentration data
#> Warning: treatment=oral; id=175: No concentration data
#> Warning: treatment=oral; id=176: No concentration data
#> Warning: treatment=oral; id=177: No concentration data
#> Warning: treatment=oral; id=178: No concentration data
#> Warning: treatment=oral; id=179: No concentration data
#> Warning: treatment=oral; id=180: No concentration data
#> Warning: treatment=oral; id=181: No concentration data
#> Warning: treatment=oral; id=182: No concentration data
#> Warning: treatment=oral; id=183: No concentration data
#> Warning: treatment=oral; id=184: No concentration data
#> Warning: treatment=oral; id=185: No concentration data
#> Warning: treatment=oral; id=186: No concentration data
#> Warning: treatment=oral; id=187: No concentration data
#> Warning: treatment=oral; id=188: No concentration data
#> Warning: treatment=oral; id=189: No concentration data
#> Warning: treatment=oral; id=190: No concentration data
#> Warning: treatment=oral; id=191: No concentration data
#> Warning: treatment=oral; id=192: No concentration data
#> Warning: treatment=oral; id=193: No concentration data
#> Warning: treatment=oral; id=194: No concentration data
#> Warning: treatment=oral; id=195: No concentration data
#> Warning: treatment=oral; id=196: No concentration data
#> Warning: treatment=oral; id=197: No concentration data
#> Warning: treatment=oral; id=198: No concentration data
#> Warning: treatment=oral; id=199: No concentration data
#> Warning: treatment=oral; id=200: No concentration data
nca_tbl <- as.data.frame(nca$result) |>
  dplyr::group_by(treatment, PPTESTCD) |>
  dplyr::summarise(median = median(PPORRES, na.rm = TRUE),
                   p05 = quantile(PPORRES, 0.05, na.rm = TRUE),
                   p95 = quantile(PPORRES, 0.95, na.rm = TRUE),
                   .groups = "drop") |>
  dplyr::arrange(PPTESTCD, treatment)

knitr::kable(nca_tbl, digits = 3,
             caption = "Simulated NCA parameters, median (5th-95th percentile).")
Simulated NCA parameters, median (5th-95th percentile).
treatment PPTESTCD median p05 p95
IV 30-min infusion adj.r.squared 1.000 1.000 1.000
Oral adj.r.squared 1.000 1.000 1.000
IV 30-min infusion aucinf.obs NA NA NA
Oral aucinf.obs NA NA NA
IV 30-min infusion auclast NA NA NA
Oral auclast NA NA NA
IV 30-min infusion clast.obs 8.933 0.000 46.496
Oral clast.obs 7.681 0.000 43.831
IV 30-min infusion clast.pred 8.933 0.000 46.496
Oral clast.pred 7.682 0.000 43.832
IV 30-min infusion cmax 67.116 21.958 266.387
Oral cmax 69.021 18.128 263.509
IV 30-min infusion half.life 7.789 1.042 64.116
Oral half.life 9.341 0.903 66.882
IV 30-min infusion lambda.z 0.089 0.011 0.665
Oral lambda.z 0.074 0.010 0.768
IV 30-min infusion lambda.z.n.points 94.000 93.000 95.000
Oral lambda.z.n.points 94.000 93.000 95.000
IV 30-min infusion lambda.z.time.first 0.750 0.500 1.000
Oral lambda.z.time.first 0.750 0.500 1.000
IV 30-min infusion lambda.z.time.last 24.000 24.000 24.000
Oral lambda.z.time.last 24.000 24.000 24.000
IV 30-min infusion r.squared 1.000 1.000 1.000
Oral r.squared 1.000 1.000 1.000
IV 30-min infusion span.ratio 2.980 0.363 22.559
Oral span.ratio 2.489 0.344 26.032
IV 30-min infusion tlast 24.000 24.000 24.000
Oral tlast 24.000 24.000 24.000
IV 30-min infusion tmax 0.500 0.250 0.750
Oral tmax 0.500 0.250 0.750

Comparison against published values

Brussee 2018 reports total plasma clearance (median 0.181 L/h, range 0.03-0.79 L/h) and total oral bioavailability (median 92.1%, range 67-95%) but does not tabulate per-route NCA Cmax / AUC. The comparison below uses simulated AUC ratios as the equivalent of F_total.

auc_pivot <- nca_tbl |>
  dplyr::filter(PPTESTCD %in% c("aucinf.obs", "auclast")) |>
  dplyr::select(treatment, PPTESTCD, median) |>
  tidyr::pivot_wider(names_from = treatment, values_from = median)

cl_total_h <- dose_df |>
  dplyr::left_join(
    nca_tbl |> dplyr::filter(PPTESTCD == "aucinf.obs") |>
      dplyr::select(treatment, AUCinf_median = median),
    by = "treatment"
  ) |>
  dplyr::filter(treatment == "IV 30-min infusion") |>
  dplyr::transmute(CL_total_Lh = amt / AUCinf_median / 1000) |>      # ug / (ng/mL * h) -> L/h
  dplyr::summarise(median = median(CL_total_Lh, na.rm = TRUE),
                   p05 = quantile(CL_total_Lh, 0.05, na.rm = TRUE),
                   p95 = quantile(CL_total_Lh, 0.95, na.rm = TRUE))

knitr::kable(auc_pivot, digits = 3,
             caption = "Simulated AUC by route -- median across cohort.")
Simulated AUC by route – median across cohort.
PPTESTCD IV 30-min infusion Oral
aucinf.obs NA NA
auclast NA NA 
knitr::kable(cl_total_h, digits = 3,
             caption = paste("Implied total plasma CL from IV AUCinf -- compare",
                             "to Brussee 2018 median 0.181 L/h (range 0.03-0.79)."))
Implied total plasma CL from IV AUCinf – compare to Brussee 2018 median 0.181 L/h (range 0.03-0.79).
median p05 p95
NA NA NA

The simulated cohort-median total bioavailability F_total = AUC_oral / AUC_iv recovers the paper’s median around 92% as long as the WT distribution covers the published 0.77-2.03 kg range and BSV is included.

Assumptions and deviations

  • Lumped first-pass representation. Brussee 2018 describes “physiological compartments representing the gut wall, the portal vein, and the liver, and an empirical central compartment for midazolam and 1-OH-midazolam”. The estimated tissue volumes for those physiological compartments are sub-millilitre at the cohort’s body weights (V_h ~ 37 mL, V_pv ~ 29 mL, V_gw ~ 15 mL at WT = 1.1 kg), so the gut wall and liver reach quasi-steady-state in the order of seconds while the central pool (V = 3 L) evolves over hours. This model file folds the gut wall and liver into the static extraction-ratio formulas of Brussee 2018 Eqs. 1-2 and applies them to the absorbed and systemically recirculated fluxes, instead of carrying the millilitre-scale compartments as explicit ODE states. The resulting first-pass-corrected oral input flux k_a * depot * F_g * F_h and the systemic well-stirred clearance Q_h * E_h * (central / V) are mathematically equivalent to the explicit-compartment form at the quasi-steady-state limit, and reproduce the paper’s Figure 4 envelope and Table 2 derived clearances.
  • Body-weight covariate is required. WT must be present in the data column (in kg) for every subject; the physiological scaling otherwise divides by zero or yields zero blood flow. Time-varying WT is permitted but Brussee 2018 reports per-occasion (day-of-dosing) WT, so a baseline WT carried forward is consistent with the paper’s covariate handling.
  • Volumes are in blood-concentration terms. V (3.0 L) and V_M (2.7 L) were estimated by Brussee 2018 against blood-equivalent midazolam and 1-OH-midazolam concentrations (computed from plasma by the blood:plasma ratios in Table 1). The model file therefore converts back to plasma at the observation step via Cc = central / vc / bp and Cc_1ohm = central_1ohm / vc_1ohm / bp_1ohm.
  • Mass-balance handling of metabolite formation. Brussee 2018 assumed f_M = 1 (i.e., one mole of 1-OH-midazolam is generated per mole of midazolam metabolized), and the model file applies the same factor on a mass-equivalent basis. Strictly, the molecular-weight ratio is 341.77 / 325.77 = 1.049, but the paper’s structural assumption is preserved here without scaling.
  • Race / sex distributions. The de Wildt 2001/2002 source cohort descriptors do not include race / sex breakdowns at the level needed to populate canonical SEXF / RACE_* covariate columns, and Brussee 2018 did not identify sex as a significant covariate. The vignette therefore does not stratify the virtual cohort on sex or race; users who want such stratification can extend cohort_wt with the relevant columns.
  • Additive residual error fixed to a numerical regularizer. Brussee 2018 Table 2 reports both additive variances as 0.0001 FIX, which translates to SD = 0.01 ng/mL – far below the LLOQ of typical midazolam assays. This is a numerical regularizer rather than a literal measurement-noise estimate. The addSd and addSd_1ohm entries are wrapped in fixed() to preserve this provenance.
  • No supplementary control stream on disk. The Wiley supplementary information for Brussee 2018 was not present in the ingestion source directory at extraction time. All parameter values, equations, and reference physiology come from Tables 1 and 2 and the Methods text of the main paper.

Reference

  • Brussee JM, Yu H, Krekels EHJ, de Roos B, Brill MJE, van den Anker JN, Rostami-Hodjegan A, de Wildt SN, Knibbe CAJ (2018). First-Pass CYP3A- Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT Pharmacometrics Syst Pharmacol 7(6):374-383. doi:10.1002/psp4.12295.