(R)-[11C]verapamil rat PET PK with kainate / tariquidar covariates (Syvanen 2011)

Model and source

• Citation: Syvanen S, Luurtsema G, Molthoff CFM, Windhorst AD, Huisman MC, Lammertsma AA, Voskuyl RA, de Lange ECM. (R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus. BMC Med Imaging. 2011;11:1. doi:[10.1186/1471-2342-11-1](https://doi.org/10.1186/1471-2342-11-1).
• Article: https://doi.org/10.1186/1471-2342-11-1 (open-access).

This vignette validates the preclinical (rat, male Sprague-Dawley) population mixed-effects popPK model for (R)-[11C]verapamil published in Syvanen et al. (2011), as fit to plasma (blood) and whole-brain VOI PET time-activity curves under four experimental arms (saline-control vs kainate-induced post-status-epilepticus state, each crossed with vehicle vs tariquidar P-glycoprotein inhibition). The structural model has two layers (paper Figure 3 schematic):

• a three-compartment plasma disposition (central + peripheral1 + peripheral2, parameterised as Vc / Vp1 / Vp2 and inter-compartmental clearances Q1 / Q2, with systemic clearance CL cleared from central);
• a two-compartment whole-brain layer (brain_csf = the fast-exchange brain compartment connected to plasma via asymmetric Qin (into brain) and Qout (out of brain); brain_deep = the deep-brain compartment connected to brain_csf only, via symmetric Qbr).

Plasma time-activity curves are complete-metabolite-corrected before model fitting (paper Methods, equation 2a), so the structural model describes intact (R)-[11C]verapamil only. Body weight is the only continuous covariate (allometric on plasma CL, reference weight 0.3084 kg – the mean across all 42 successfully scanned rats). Tariquidar co-administration multiplies Vp1 by 1.20, Vbr1 by 2.41, and Qin by 12.0; the kainate-induced post-SE state multiplies Vbr1 by 1.32 (no significant effect on Qin or Qout); both categorical covariate effects use the paper’s theta^COV multiplicative form (Equation 5 in the paper).

Population

42 successfully scanned male Sprague-Dawley rats (Harlan, Horst, The Netherlands), body weight 200-224 g at arrival and 308 +/- 31 g (mean +/- SD) on the experimental day, distributed across four arms:

• saline + vehicle (n = 10, mean body weight 327 +/- 26 g);
• kainate + vehicle (n = 11, mean 292 +/- 33 g);
• saline + tariquidar (n = 10, mean 326 +/- 25 g);
• kainate + tariquidar (n = 11, mean 293 +/- 24 g).

Of an original 50 animals, 8 were excluded (4 died from the kainate-induction protocol, 1 did not respond to kainate, 3 had technical issues such as scanner movement or extravascular tracer injection). Kainate-treated rats received repeated intraperitoneal injections of kainic acid (10 mg/kg loading, then 5 mg/kg every 30-60 min until stage IV-V seizures by Racine scale, or 30 mg/kg total) 7 days prior to scanning. Tariquidar-treated rats received a 15 mg/kg IV bolus 20-30 min before the (R)-[11C]verapamil injection. The same metadata are available programmatically via readModelDb("Syvanen_2011_verapamil_rat")$population.

Source trace

The per-parameter origin is recorded inline next to each ini() entry in inst/modeldb/specificDrugs/Syvanen_2011_verapamil_rat.R. The table below collects everything in one place for review.

Equation / parameter	Value	Source location
d/dt(central)	n/a	Plasma 3-cmt + 2 cross-BBB flows; paper Figure 3 schematic, Methods ‘NONMEM model’
d/dt(peripheral1)	n/a	Plasma 3-cmt; paper Figure 3
d/dt(peripheral2)	n/a	Plasma 3-cmt; paper Figure 3
d/dt(brain_csf)	n/a	Brain 2-cmt; paper Figure 3
d/dt(brain_deep)	n/a	Brain 2-cmt; paper Figure 3
lvc (Vc)	log(22.8) mL	Paper Table 3: Vc = 22.8 mL (SE 2.41)
lvp (Vp1)	log(504) mL	Paper Table 3: Vp1 = 504 mL (SE 40.7)
lvp2 (Vp2)	log(70.2) mL	Paper Table 3: Vp2 = 70.2 mL (SE 9.91)
lcl (CL)	log(14.7) mL/min	Paper Table 3: CL = 14.7 mL/min (SE 0.681)
lq (Q1)	log(16.1) mL/min	Paper Table 3: Q1 = 16.1 mL/min (SE 1.75)
lq2 (Q2)	log(22.7) mL/min	Paper Table 3: Q2 = 22.7 mL/min (SE 3.34)
lvbr1 (Vbr1)	log(7.23) mL	Paper Table 3: Vbr1 = 7.23 mL (SE 2.00)
lvbr2 (Vbr2)	log(10.7) mL	Paper Table 3: Vbr2 = 10.7 mL (SE 2.22)
lqin (Qin)	log(1.75) mL/min	Paper Table 3: Qin = 1.75 mL/min (SE 0.26)
lqout (Qout)	log(1.81) mL/min	Paper Table 3: Qout = 1.81 mL/min (SE 0.283)
lqbr (Qbr)	log(0.692) mL/min	Paper Table 3: Qbr = 0.692 mL/min (SE 0.143)
e_conmed_tariquidar_vp	log(1.20)	Paper Table 3: tariquidar covariate on Vp1 = 1.20 (SE 0.119); theta^COV form
e_conmed_tariquidar_vbr1	log(2.41)	Paper Table 3: tariquidar covariate on Vbr1 = 2.41 (SE 0.505)
e_conmed_tariquidar_qin	log(12.0)	Paper Table 3: tariquidar covariate on Qin = 12.0 (SE 0.554)
e_dis_postse_kainate_vbr1	log(1.32)	Paper Table 3: kainate (rat-group) covariate on Vbr1 = 1.32 (SE 0.416)
e_wt_cl	1.98	Paper Table 3 + Equation 4: weight allometric exponent on CL = 1.98, ref WT = 0.3084 kg
etalvc	0.175	Paper Table 3: IIV(Vc) variance = 0.175 (SE 0.085)
etalvp2	0.036	Paper Table 3: IIV(Vp2) variance = 0.036 (SE 0.034)
etalcl	0.065	Paper Table 3: IIV(CL) variance = 0.065 (SE 0.016)
etalq	0.220	Paper Table 3: IIV(Q1) == IIV(Q2) = 0.220 (SE 0.073); shared eta encoding
etalvbr	0.115	Paper Table 3: IIV(Vbr1) == IIV(Vbr2) = 0.115 (SE 0.054); shared eta encoding
propSd	0.118	Paper Table 3: residual error ‘blood’ = 0.118 (SE 0.0152) (proportional model)
propSd_Cbrain	0.226	Paper Table 3: residual error ‘brain’ = 0.226 (SE 0.0354) (proportional model)

Virtual cohort

A four-arm virtual cohort matches the paper’s design (n = 10 or 11 per arm, replicated 20-fold for tighter VPC percentile bands; arm-mean body weights from Table 1). Each rat receives a single intravenous bolus of 20 MBq (R)-[11C]verapamil at t = 0; observations are sampled every 30 seconds across the full 60 minute PET acquisition window. The tariquidar pre-dose is captured via the CONMED_TARIQUIDAR covariate (the structural model treats tariquidar exposure as binary, justified by the paper’s observation that tariquidar plasma concentrations did not differ between saline and kainate arms at 2 h post-dose).

set.seed(2011)

arm_design <- tibble::tribble(
  ~arm,                          ~n,   ~WT_kg,    ~CONMED_TARIQUIDAR, ~DIS_POSTSE_KAINATE,
  "saline + vehicle",            10L,  0.327,     0L,                 0L,
  "kainate + vehicle",           11L,  0.292,     0L,                 1L,
  "saline + tariquidar",         10L,  0.326,     1L,                 0L,
  "kainate + tariquidar",        11L,  0.293,     1L,                 1L
)

# Dose: 20 MBq IV bolus (paper Table 1 reports 20.8 +/- 4.5 MBq mean across arms).
dose_mbq          <- 20
sim_duration_min  <- 60
obs_times         <- seq(0.5, sim_duration_min, by = 0.5)

make_arm <- function(arm_label, n, wt_kg, tariq, kainate, id_offset = 0L) {
  # Dosing rows (evid = 1) + observation rows (evid = 0).
  ids <- id_offset + seq_len(n)
  dose_rows <- tibble::tibble(
    id   = ids,
    time = 0,
    amt  = dose_mbq,
    evid = 1L,
    cmt  = "central",
    WT                  = wt_kg,
    CONMED_TARIQUIDAR   = tariq,
    DIS_POSTSE_KAINATE  = kainate,
    arm                 = arm_label
  )
  obs_rows <- tidyr::expand_grid(
    id   = ids,
    time = obs_times
  ) |>
    dplyr::mutate(
      amt  = 0,
      evid = 0L,
      cmt  = "Cc",
      WT                  = wt_kg,
      CONMED_TARIQUIDAR   = tariq,
      DIS_POSTSE_KAINATE  = kainate,
      arm                 = arm_label
    )
  dplyr::bind_rows(dose_rows, obs_rows)
}

n_replicates  <- 20L
events_list   <- list()
offset_cursor <- 0L
for (rep in seq_len(n_replicates)) {
  for (i in seq_len(nrow(arm_design))) {
    a <- arm_design[i, ]
    events_list[[length(events_list) + 1L]] <- make_arm(
      arm_label  = a$arm,
      n          = a$n,
      wt_kg      = a$WT_kg,
      tariq      = a$CONMED_TARIQUIDAR,
      kainate    = a$DIS_POSTSE_KAINATE,
      id_offset  = offset_cursor
    )
    offset_cursor <- offset_cursor + a$n
  }
}
events_rat <- dplyr::bind_rows(events_list)
stopifnot(!anyDuplicated(unique(events_rat[, c("id", "time", "evid")])))

Simulation

mod <- readModelDb("Syvanen_2011_verapamil_rat")

sim <- rxode2::rxSolve(mod, events = events_rat,
                       keep = c("arm", "WT", "CONMED_TARIQUIDAR", "DIS_POSTSE_KAINATE")) |>
  as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'

A deterministic typical-value trace per arm (zeroed random effects) is used for the macroconstant validation later in this vignette:

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

# One representative rat per arm for the typical-value sim
events_typical <- arm_design |>
  dplyr::mutate(id = seq_len(dplyr::n())) |>
  dplyr::rowwise() |>
  dplyr::do({
    make_arm(arm_label = .$arm, n = 1L, wt_kg = .$WT_kg,
             tariq = .$CONMED_TARIQUIDAR, kainate = .$DIS_POSTSE_KAINATE,
             id_offset = .$id - 1L)
  }) |>
  dplyr::ungroup()
stopifnot(!anyDuplicated(unique(events_typical[, c("id", "time", "evid")])))

sim_typical <- rxode2::rxSolve(mod_typical, events_typical,
                               keep = c("arm", "WT", "CONMED_TARIQUIDAR", "DIS_POSTSE_KAINATE")) |>
  as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalvc', 'etalvp2', 'etalcl', 'etalq', 'etalvbr'
#> Warning: multi-subject simulation without without 'omega'

Replicate Figure 1 (mean whole-brain SUV by arm)

Figure 1 of Syvanen 2011 plots mean +/- SD whole-brain SUV (radioactivity normalised to injected dose and animal weight) over 60 min for the four rat groups. The published figure shows vehicle (saline / kainate) brain uptake plateauing at low SUV (<= 1) and tariquidar-treated rats reaching SUV ~3-4. Here we reproduce the typical-value trace per arm; SUV is computed as Cbrain * WT_g / dose_MBq, where WT_g = WT_kg * 1000 (paper SUV convention).

sim_typical_with_suv <- sim_typical |>
  dplyr::filter(time > 0) |>
  dplyr::mutate(SUV_brain = Cbrain * (WT * 1000) / dose_mbq,
                SUV_plasma = Cc * (WT * 1000) / dose_mbq)

ggplot(sim_typical_with_suv, aes(time, SUV_brain, colour = arm)) +
  geom_line(linewidth = 0.9) +
  labs(x = "Time (min)", y = "Whole-brain SUV (unitless)",
       title = "Figure 1 replication: mean whole-brain (R)-[11C]verapamil SUV by treatment arm",
       caption = "Replicates Figure 1 of Syvanen 2011 (typical-value trace, IIV zeroed). Tariquidar arms (Group 3 + 4) reach SUV ~3-4 at the 60-min plateau; vehicle arms (Group 1 + 2) plateau below 1 SUV.")

A stochastic VPC version using the full virtual cohort (with IIV and residual error):

vpc_brain <- sim |>
  dplyr::filter(time > 0) |>
  dplyr::mutate(SUV_brain = Cbrain * (WT * 1000) / dose_mbq) |>
  dplyr::group_by(arm, time) |>
  dplyr::summarise(
    Q05 = quantile(SUV_brain, 0.05, na.rm = TRUE),
    Q50 = quantile(SUV_brain, 0.50, na.rm = TRUE),
    Q95 = quantile(SUV_brain, 0.95, na.rm = TRUE),
    .groups = "drop"
  )

ggplot(vpc_brain, aes(time, Q50, colour = arm, fill = arm)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.2, colour = NA) +
  geom_line(linewidth = 0.7) +
  labs(x = "Time (min)", y = "Whole-brain SUV (unitless)",
       title = "Figure 1 stochastic VPC: median + 5th-95th percentile per arm",
       caption = "Solid line = median; ribbon = 5-95 percentile of the simulated cohort (20-fold replicate of Syvanen 2011 Table 1 design).")

Replicate Table 2 (2-compartment popPK macroconstants and Kp)

Table 2 of Syvanen 2011 reports per-group K1, k2, k3, k4, and Kp macroconstants computed from the same NONMEM popPK fit. The table footer states the closed-form mapping from the structural Table 3 estimates: K1 = Qin / (Vbr1 + Vbr2), k2 = Qout / Vbr1, k3 = Qbr / Vbr1, k4 = Qbr / Vbr2, and (from the steady-state equilibrium of the asymmetric BBB) Kp = Qin / Qout. Reproducing those formulas directly from the typical-value parameters per arm:

table3_typical <- function(tariq, kainate) {
  Vc   <- 22.8
  Vp1  <- 504 * (1.20)^tariq
  Vp2  <- 70.2
  CL   <- 14.7        # weight-effect ignored at the typical-value Reference WT
  Q1   <- 16.1
  Q2   <- 22.7
  Vbr1 <- 7.23 * (2.41)^tariq * (1.32)^kainate
  Vbr2 <- 10.7
  Qin  <- 1.75 * (12.0)^tariq
  Qout <- 1.81
  Qbr  <- 0.692
  tibble::tibble(
    K1 = Qin / (Vbr1 + Vbr2),
    k2 = Qout / Vbr1,
    k3 = Qbr  / Vbr1,
    k4 = Qbr  / Vbr2,
    Kp = Qin / Qout
  )
}

macro_pred <- arm_design |>
  dplyr::rowwise() |>
  dplyr::mutate(macro = list(table3_typical(CONMED_TARIQUIDAR, DIS_POSTSE_KAINATE))) |>
  tidyr::unnest(macro) |>
  dplyr::select(arm, K1, k2, k3, k4, Kp)

knitr::kable(
  macro_pred,
  digits = 3,
  caption = "Macroconstants derived from Table 3 typical-value parameters per arm."
)

Macroconstants derived from Table 3 typical-value parameters per arm.

arm	K1	k2	k3	k4	Kp
saline + vehicle	0.098	0.250	0.096	0.065	0.967
kainate + vehicle	0.086	0.190	0.073	0.065	0.967
saline + tariquidar	0.747	0.104	0.040	0.065	11.602
kainate + tariquidar	0.623	0.079	0.030	0.065	11.602

A direct side-by-side against the published Table 2 means ((R)-[11C]verapamil, Model - 2 comp PopPK row block):

Quantity / arm	Paper Table 2 (mean +/- SD)	Model (typical-value, this vignette)
K1 saline + vehicle	0.10 (0.02)	0.1
K1 kainate + vehicle	0.10 (0.02)	0.09
K1 saline + tariquidar	0.75 (0.14)	0.75
K1 kainate + tariquidar	0.62 (0.12)	0.62
k2 saline + vehicle	0.25 (0.08)	0.25
k2 kainate + vehicle	0.25 (0.08)	0.19
k2 saline + tariquidar	0.10 (0.04)	0.1
k2 kainate + tariquidar	0.08 (0.03)	0.08
k3 saline + vehicle	0.10 (0.03)	0.1
k3 saline + tariquidar	0.04 (0.02)	0.04
k4 saline + tariquidar	0.06 (0.02)	0.06
Kp saline + vehicle	0.97 (0.21)	0.97
Kp saline + tariquidar	11.6 (2.6)	11.6
Kp kainate + tariquidar	11.6 (2.6)	11.6

The tariquidar-arm macroconstants reproduce the published Table 2 values to two decimal places; the vehicle-arm K1, k2, k3 for the kainate group are lower than the saline group in the model (because the kainate covariate inflates Vbr1 by 32%), whereas Table 2 reports identical macroconstant means for the saline-vehicle and kainate-vehicle groups. This discrepancy is consistent with one of two readings of the paper – see Assumptions and deviations.

PKNCA validation (plasma)

PKNCA is run on the simulated plasma Cc curves per arm. Following the IV-bolus single-dose recipe (no extrapolation needed beyond the 60-minute observation window because the PET acquisition ends well before the terminal phase is fully resolved in plasma):

sim_nca <- sim |>
  dplyr::filter(time > 0, !is.na(Cc)) |>
  dplyr::transmute(id, time, Cc, arm)

conc_obj <- PKNCA::PKNCAconc(sim_nca, Cc ~ time | arm + id)

dose_df <- events_rat |>
  dplyr::filter(evid == 1L) |>
  dplyr::transmute(id, time, amt, arm)

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

intervals <- data.frame(
  start       = 0,
  end         = 60,
  cmax        = TRUE,
  tmax        = TRUE,
  auclast     = TRUE
)

nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_res  <- PKNCA::pk.nca(nca_data)
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#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.5) is not allowed

nca_summary <- summary(nca_res)
knitr::kable(nca_summary, caption = "Simulated plasma NCA by treatment arm (0 - 60 min window).")

Simulated plasma NCA by treatment arm (0 - 60 min window).

start	end	arm	N	auclast	cmax	tmax
0	60	kainate + tariquidar	220	NC	0.173 [39.0]	0.500 [0.500, 0.500]
0	60	kainate + vehicle	220	NC	0.234 [47.8]	0.500 [0.500, 0.500]
0	60	saline + tariquidar	200	NC	0.152 [41.9]	0.500 [0.500, 0.500]
0	60	saline + vehicle	200	NC	0.234 [42.5]	0.500 [0.500, 0.500]

Assumptions and deviations

• Compartment names brain_csf and brain_deep are paper-named rather than canonical. Same convention rationale as Xie 2000: the brain layer is asymmetric (Qin != Qout across the BBB) and the deep brain compartment connects only to the fast-exchange brain compartment, so neither matches the symmetric peripheral semantics. Naming them brain_csf and brain_deep follows the Xie 2000 m3g_rat precedent; the paper’s labels are Vbr1 and Vbr2, with no explicit anatomical interpretation beyond “the brain compartment exchanging directly with plasma” and “the deeper brain compartment”. checkModelConventions() will emit one compartment warning per name (accepted by design).
• Brain output Cbrain is paper-named. The whole-brain VOI observation is the sum of activity in brain_csf and brain_deep divided by their summed volumes. The nlmixr2lib observation register includes Cbrain_<region> for region-specific outputs but no canonical name for a multi-compartment whole-brain aggregate, so the model declares propSd_Cbrain via the paper_specific_residual_sds mechanism. Accepted by design.
• Paper-specific PK-parameter names lvbr1, lvbr2, lqin, lqout, lqbr. The brain-layer asymmetric BBB structure does not collapse to canonical vc / vp / vp2 / q semantics, so paper-faithful names are used. Same precedent as Xie 2000 (lvubr1, lvubr2, lcluin, lcluout, lqbr). checkModelConventions() will report one warning per non-canonical PK-parameter name (accepted by design).
• Shared etas for Q1/Q2 and Vbr1/Vbr2. Table 3 of Syvanen 2011 reports the inter-individual variability of Q1 and Q2 with identical numeric values (0.220 (0.073)) and the IIV of Vbr1 and Vbr2 with identical numeric values (0.115 (0.054)). Identical SE-to-the-same-decimal-place is essentially impossible if two independent etas were estimated separately (each variance estimate carries its own SE distribution under FOCE-I), so the model encodes these as shared etas (Q1 and Q2 share a single etalq; Vbr1 and Vbr2 share a single etalvbr). The alternative interpretation – two independent etas constrained to be numerically identical – is mathematically equivalent at the population mean but underestimates joint variability if Q1 and Q2 are treated as independent draws. If the paper actually fit independent etas, the per-rat simulated profiles will be slightly less correlated than the published fit; the typical-value (zeroed-IIV) predictions are unaffected.
• Table 2 vs Table 3 macroconstant inconsistency for the kainate + vehicle group. Table 2 reports identical macroconstants (K1 = 0.10, k2 = 0.25, k3 = 0.10) for the saline-vehicle (Group 1) and kainate-vehicle (Group 2) arms, while Table 3 + the table-footer macroconstant formulas imply that the 32% kainate-induced increase in Vbr1 should reduce k2 from 0.250 to 0.190, k3 from 0.096 to 0.073, and K1 from 0.098 to 0.087 in the kainate-vehicle group. The model file implements Table 3 + Equation 5 literally (kainate covariate applies to Vbr1 regardless of tariquidar status, as Syvanen 2011 Discussion paragraph 5 explicitly states “rat group as covariate for the brain distribution volume, Vbr1, did improve the model fit significantly and increased Vbr1 with 32% in kainate treated compared to saline treated rats”), so the model-predicted macroconstants for Group 2 differ from Table 2 by ~24-27%. Possible explanations: (a) Table 2 reports macroconstants computed from the structural model WITHOUT covariate effects (i.e., as a model-comparison baseline), with the kainate effect captured only through the Vbr1 fractional change reported in Table 3; (b) Table 2 reports per-individual empirical Bayes estimates averaged within each group, with the eta variation partially compensating for the typical-value shift; (c) the Table 2 rendering has a typesetting issue. The model file implements the interpretation consistent with the paper’s stated structural description (kainate uniformly inflates Vbr1 by 1.32 across both tariquidar conditions); the tariquidar-arm macroconstants reproduce Table 2 to two decimal places under this interpretation, supporting it. Users relying on the kainate-vehicle macroconstants matching Table 2 exactly should be aware of this discrepancy.
• Body weight treated as time-fixed. The Syvanen 2011 dataset records one body-weight value per animal on the experimental day; the model treats WT as a per-subject baseline covariate rather than time-varying. The 60-minute PET acquisition window is short enough that weight changes are negligible regardless.
• Constant-rate IV bolus vs the paper’s bolus injection. Syvanen 2011 administered (R)-[11C]verapamil as a single intravenous bolus over 30 seconds (paper Methods, p1785: “The emission scan was started 30 seconds before an injection …”). The vignette simulation uses a true zero-duration bolus event (evid = 1, no rate column). This causes a discontinuity at t = 0 in the simulated Cc that the paper’s 30-second push would smooth out, but the integrated AUC, Cmax (at first sample), and brain time-activity curve from t = 0.5 min onward are unaffected.
• All 42 rats pooled into a virtual cohort with arm-mean body weights. Table 1 of Syvanen 2011 reports per-arm mean body weights (327, 292, 326, 293 g) and SD (~25-33 g). The vignette virtual cohort uses the per-arm means as a fixed weight per animal within an arm rather than a per-subject body-weight distribution. This collapses the WT-driven CL spread inside each arm (the model’s per-rat CL scales as (WT/0.3084)^1.98, so a 30 g SD around a 308 g mean gives roughly +/- 18% spread in CL) into the residual variability captured by etalcl. Users who want a more realistic spread can replace the constant WT_kg with rnorm(n, mean = arm_WT, sd = arm_WT_SD).
• The model is fit to metabolite-corrected plasma curves and describes intact (R)-[11C]verapamil only. Paper Methods (equation 2a) describe the complete-metabolite-correction applied to all plasma samples before model fitting. The model therefore does NOT predict total plasma radioactivity (which would include 11C-labelled N-dealkylated, O-demethylated, and N-demethylated metabolites). Users interpreting simulated plasma Cc should treat it as intact-tracer activity per mL.