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Ketorolac (Valitalo 2017)

Source: vignettes/articles/Valitalo_2017_ketorolac.Rmd
Valitalo_2017_ketorolac.Rmd

Model and source

  • Citation: Valitalo PA, Kemppainen H, Kulo A, Smits A, van Calsteren K, Olkkola KT, de Hoon J, Knibbe CAJ, Allegaert K (2017). Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics. Br J Clin Pharmacol 83(9):1966-1975. doi:10.1111/bcp.13311.
  • Article: https://doi.org/10.1111/bcp.13311
  • Source files on disk: the published PDF (Vlitalo_2017_Body_weight_gender_and_pregnancy_affect__c9886c.pdf). No supplementary NONMEM control stream was bundled with the task; all parameter values come from the paper’s Table 2 final-model column and the Methods (equations 1-6).
mod_fn <- readModelDb("Valitalo_2017_ketorolac")
mod    <- rxode2::rxode2(mod_fn())

Population

Valitalo 2017 pooled the data from two single-IV-bolus studies of racemic ketorolac tromethamine (Methods, page 1967): the Leuven (Belgium) study enrolled 41 women immediately post-Caesarean section (the “women at delivery” / WAD subgroup), 8 of whom were re-studied 4-5 months later (the “postpartum” subgroup, paired sessions on the same 8 women), and a further 8 nonpregnant healthy female volunteers. The Helsinki (Finland) study contributed 12 men and 6 nonpregnant women, ASA physical status I-II, undergoing minor eye surgery. After removing the postpartum sessions as repeats on women already counted in the at-delivery subgroup, the pooled analysis covers 67 unique adults: 41 + 14 = 55 women (82%) and 12 men (18%); pooled age range 19-44 years and weight range 40-106 kg (Valitalo 2017 Table 1). Race / ethnicity composition is not reported.

Doses were 30 mg racemic ketorolac tromethamine (equivalent to 20.345 mg pure ketorolac per dose) given as an IV bolus at the end of surgery in Leuven, and 0.5 mg/kg over 30 s in Helsinki. The data were modelled as half of the racemic dose entering the R-enantiomer compartment and half entering the S-enantiomer compartment, with no interconversion (Valitalo 2017 Methods, page 1968).

local({
  fbody <- body(mod_fn)
  meta_env <- new.env()
  for (stmt in as.list(fbody)[-1]) {
    if (is.call(stmt) && length(stmt) >= 1 &&
        identical(stmt[[1]], as.name("<-"))) {
      eval(stmt, envir = meta_env)
    } else {
      break
    }
  }
  cat("Population:\n")
  str(meta_env$population, max.level = 1)
  cat("\nCovariates:\n")
  str(meta_env$covariateData, max.level = 1)
})
#> Population:
#> List of 10
#>  $ n_subjects    : int 67
#>  $ n_studies     : int 2
#>  $ age_range     : chr "19-44 years"
#>  $ weight_range  : chr "40-106 kg"
#>  $ sex_female_pct: num 82
#>  $ race_ethnicity: NULL
#>  $ disease_state : chr "Postoperative analgesia. Pooled analysis of two single-IV-bolus studies: (i) Leuven (Belgium): 41 women immedia"| __truncated__
#>  $ dose_range    : chr "Single IV bolus of racemic ketorolac tromethamine: 30 mg (Leuven; equivalent to 20.345 mg pure ketorolac per do"| __truncated__
#>  $ regions       : chr "Leuven, Belgium and Helsinki, Finland"
#>  $ notes         : chr "Demographics from Valitalo 2017 Table 1: women at delivery n = 41, age 33 (25-44) y, weight 73.9 (40-106) kg; p"| __truncated__
#> 
#> Covariates:
#> List of 3
#>  $ WT  :List of 6
#>  $ PREG:List of 6
#>  $ SEXF:List of 6

Source trace

Every parameter and equation traces back to a specific location in Valitalo 2017. The structural model is described in the Methods (pages 1967-1968) and the parameter values are read from Table 2 (“Final model” column).

Equation / parameter Value Source location
3-compartment IV structural model for each enantiomer – Methods, page 1967: “A three-compartment structural model was selected for both enantiomers.”
No interconversion between R- and S-enantiomers – Methods, page 1968: “No interconversion between ketorolac enantiomers was assumed because conversion from S to R has been reported to be minimal (6.5%), and conversion from R to S is non-existent.”
Half of racemic dose into each enantiomer compartment – Methods, page 1968: “The data were modelled based on administering half of the racemic ketorolac dose as the R-enantiomer and half as the S-enantiomer.”
lcl_r = log(1.12) (L/h) 1.12 Table 2 final, CL_R (RSE 5.95%)
lvc_r = log(3.4) (L) 3.4 Table 2 final, V1_R (RSE 5.99%)
lq_r = log(3.86) (L/h) 3.86 Table 2 final, Q1_R (RSE 9.94%)
lvp_r = log(2.29) (L) 2.29 Table 2 final, V2_R (RSE 9.09%)
lq2_r = log(0.58) (L/h) 0.58 Table 2 final, Q2_R (RSE 11.8%)
lvp2_r = log(4.88) (L) 4.88 Table 2 final, V3_R (RSE 20.1%)
lcl_s = log(3.96) (L/h) 3.96 Table 2 final, CL_S (RSE 5.7%)
lvc_s = log(3.74) (L) 3.74 Table 2 final, V1_S (RSE 6.95%)
lq_s = log(20) (L/h) 20 Table 2 final, Q1_S (RSE 10.7%)
lvp_s = log(3.86) (L) 3.86 Table 2 final, V2_S (RSE 8.62%)
lq2_s = log(1.3) (L/h) 1.3 Table 2 final, Q2_S (RSE 20.5%)
lvp2_s = log(3.3) (L) 3.3 Table 2 final, V3_S (RSE 9.71%)
e_wt_cl = 0.536 (allometric) 0.536 Table 2 final, WT_CL (RSE 36.5%)
e_wt_vc_vp = 0.807 (allometric, applied to V1, V2, V3) 0.807 Table 2 final, WT_V (RSE 20.1%)
e_preg_cl = 0.554 (proportional) 0.554 Table 2 final, WAD_CL (RSE 20.4%)
e_sexf_cl = 0.363 (proportional, applied via 1 - SEXF) 0.363 Table 2 final, MS_CL (RSE 30.5%)
e_preg_vc_vp = 0.273 (proportional, applied to V1, V2, V3) 0.273 Table 2 final, WAD_V (RSE 35.6%)
Reference body weight 71 kg 71 Table 2 footnotes a-d: “weight/71”
Allometric and categorical covariate equations – Equations 5 and 6, page 1969 (power form for continuous, linear-in-indicator for categorical)
etalcl_r ~ 0.289^2 = 0.0835 omega 0.289 Table 2 final, omega(CL_R)
etalvc_r ~ 0.227^2 = 0.0515 (shared across V1_R, V2_R, V3_R) omega 0.227 Table 2 final, omega(V_R); Methods page 1968: “jointly for central and peripheral volumes of distribution (one random effect affecting multiple parameters)”
etalcl_s ~ 0.232^2 = 0.0538 omega 0.232 Table 2 final, omega(CL_S)
etalvc_s ~ 0.238^2 = 0.0566 (shared across V1_S, V2_S, V3_S) omega 0.238 Table 2 final, omega(V_S)
Combined proportional + additive residual error – Methods equations 2-4, page 1968; theta_scale = 5.1 -> f_prop = exp(5.1)/(1+exp(5.1)) ~= 0.9939
propSd_r = 0.0791, addSd_r = 0.00618 Leuven sigma_R = 0.0794 Table 2 final, sigma(Leuven, R); split via f_prop
propSd_s = 0.1097, addSd_s = 0.00857 Leuven sigma_S = 0.110 Table 2 final, sigma(Leuven, S); split via f_prop

Virtual cohort

We mirror the four published cohorts with their Table 1 median demographics and apply the structural-model covariates as time-fixed per-subject indicators (PREG, SEXF, WT). Each cohort holds 30 simulated subjects with weight drawn uniformly across the cohort’s Table 1 range. Each subject receives a single 30 mg racemic IV bolus, modelled as two simultaneous IV-bolus dose records of 15 mg each (half the racemic dose) targeting central_r and central_s respectively.

set.seed(20260509L)
n_per_cohort <- 30L

obs_times <- c(0, 0.0333, 0.083, 0.167, 0.333, 0.5,
               0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24)

build_cohort <- function(label, n, wt_low, wt_high, preg, sexf,
                         id_offset, dose_total_mg = 30) {
  ids <- id_offset + seq_len(n)
  wt  <- runif(n, wt_low, wt_high)

  # Two simultaneous IV bolus dose records per administration: half the
  # racemic dose targeted at central_r and half at central_s. Use the
  # compartment names rather than numeric indices so the data is robust
  # to ODE-declaration reordering.
  dose_rows_r <- data.frame(
    id        = ids,
    time      = 0,
    evid      = 1L,
    amt       = dose_total_mg / 2,
    cmt       = "central_r",
    treatment = label,
    PREG      = preg,
    SEXF      = sexf,
    WT        = wt,
    stringsAsFactors = FALSE
  )
  dose_rows_s <- dose_rows_r
  dose_rows_s$cmt <- "central_s"

  obs_rows <- expand.grid(
    id   = ids,
    time = obs_times,
    KEEP.OUT.ATTRS = FALSE
  )
  obs_rows$evid      <- 0L
  obs_rows$amt       <- 0
  obs_rows$cmt       <- "Cc_r"   # rxSolve still returns both Cc_r and Cc_s columns
  obs_rows$treatment <- label
  obs_rows$PREG      <- rep(preg, each = length(obs_times))
  obs_rows$SEXF      <- rep(sexf, each = length(obs_times))
  obs_rows$WT        <- rep(wt,   each = length(obs_times))

  out <- rbind(dose_rows_r, dose_rows_s, obs_rows)
  out[order(out$id, out$time, -out$evid), ]
}

events <- dplyr::bind_rows(
  build_cohort("Women at delivery",  n_per_cohort,
               wt_low = 40,   wt_high = 106,
               preg = 1L, sexf = 1L, id_offset =   0L),
  build_cohort("Postpartum",         n_per_cohort,
               wt_low = 48.8, wt_high = 87.2,
               preg = 0L, sexf = 1L, id_offset = 100L),
  build_cohort("Nonpregnant female", n_per_cohort,
               wt_low = 49,   wt_high = 74.5,
               preg = 0L, sexf = 1L, id_offset = 200L),
  build_cohort("Male",               n_per_cohort,
               wt_low = 64,   wt_high = 99,
               preg = 0L, sexf = 0L, id_offset = 300L)
)

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

Simulation

A typical-value (no-IIV, no-residual-error) replication isolates the covariate-driven differences between cohorts; a stochastic VPC then layers the published BSV on top.

mod_typical <- rxode2::zeroRe(mod)

sim_typical <- rxode2::rxSolve(
  mod_typical,
  events = events,
  keep   = c("treatment", "PREG", "SEXF", "WT")
) |>
  as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl_r', 'etalvc_r', 'etalcl_s', 'etalvc_s'
#> Warning: multi-subject simulation without without 'omega'
sim <- rxode2::rxSolve(
  mod,
  events = events,
  keep   = c("treatment", "PREG", "SEXF", "WT")
) |>
  as.data.frame()

Replicate published figures

Figure 1 – enantiomer-specific concentration-time profiles by group

Figure 1 of Valitalo 2017 shows semi-logarithmic plots of R- and S-ketorolac plasma concentrations vs time for the four populations. The replication below uses the typical-value simulation so the between-cohort contrasts (lower exposure in women at delivery, similar initial concentrations across groups, faster S-ketorolac decline) are unobscured by between-subject variability.

sim_typical |>
  tidyr::pivot_longer(c(Cc_r, Cc_s), names_to = "enantiomer",
                      values_to = "conc_mgL") |>
  dplyr::mutate(
    enantiomer = dplyr::recode(enantiomer,
                               Cc_r = "R-ketorolac",
                               Cc_s = "S-ketorolac")
  ) |>
  dplyr::filter(time > 0, conc_mgL > 0) |>
  dplyr::group_by(time, treatment, enantiomer) |>
  dplyr::summarise(
    median = median(conc_mgL, na.rm = TRUE),
    .groups = "drop"
  ) |>
  ggplot(aes(time, median, colour = treatment)) +
  geom_line(linewidth = 0.8) +
  facet_wrap(~ enantiomer, scales = "free_y") +
  scale_y_log10() +
  labs(
    x = "Time post-dose (h)",
    y = "Plasma concentration (mg/L)",
    colour = NULL,
    title = "Typical-value plasma trajectory after a single 30 mg racemic IV bolus",
    caption = paste(
      "Replicates Valitalo 2017 Figure 1 (semi-log R- and S-ketorolac",
      "concentrations by population). Women at delivery show the lowest",
      "exposure due to higher CL (+55%) and higher V (+27%); males show",
      "faster S-ketorolac decline due to higher CL (+36%); S-ketorolac",
      "decays roughly 3.5x faster than R-ketorolac across all groups."
    )
  )

sim_vpc <- sim |>
  tidyr::pivot_longer(c(Cc_r, Cc_s), names_to = "enantiomer",
                      values_to = "conc_mgL") |>
  dplyr::mutate(
    enantiomer = dplyr::recode(enantiomer,
                               Cc_r = "R-ketorolac",
                               Cc_s = "S-ketorolac")
  ) |>
  dplyr::filter(time > 0, conc_mgL > 0) |>
  dplyr::group_by(time, treatment, enantiomer) |>
  dplyr::summarise(
    p05 = quantile(conc_mgL, 0.05, na.rm = TRUE),
    p50 = quantile(conc_mgL, 0.50, na.rm = TRUE),
    p95 = quantile(conc_mgL, 0.95, na.rm = TRUE),
    .groups = "drop"
  )

ggplot(sim_vpc, aes(time, p50, colour = treatment, fill = treatment)) +
  geom_ribbon(aes(ymin = p05, ymax = p95), alpha = 0.18, colour = NA) +
  geom_line(linewidth = 0.7) +
  facet_wrap(~ enantiomer, scales = "free_y") +
  scale_y_log10() +
  labs(
    x = "Time post-dose (h)",
    y = "Plasma concentration (mg/L)",
    colour = NULL, fill = NULL,
    title = "Stochastic VPC after a single 30 mg racemic IV bolus (5%-50%-95%)",
    caption = paste(
      "Compare against Valitalo 2017 Figure 4 (VPC stratified by enantiomer).",
      "The 5%-50%-95% bands here are the simulation-only intervals; observed",
      "data percentile lines are not overlaid because individual-level data",
      "are not redistributed with the publication."
    )
  )

Figure 5 – multi-dose simulation under the SmPC regimen

Valitalo 2017 Figure 5 simulates a 10 mg loading dose followed by 20 mg every 6 h (the ketorolac Summary of Product Characteristics regimen) and contrasts (A) body-weight, (B) pregnancy, and (C) male-sex effects on concentrations. We reproduce panel B (pregnancy effect) for both enantiomers using typical-value simulation in two reference 70-kg subjects – a nonpregnant female and a woman at delivery.

mdose_n <- 1L
mdose_dose_times <- c(0, seq(6, 96, by = 6))   # 10 mg load, 20 mg q6h to 96 h
mdose_obs_times  <- seq(0, 102, by = 0.25)

build_mdose_subject <- function(label, preg, sexf, wt, id) {
  load_r <- data.frame(id = id, time = 0, evid = 1L, amt = 5,
                       cmt = "central_r", treatment = label,
                       PREG = preg, SEXF = sexf, WT = wt,
                       stringsAsFactors = FALSE)
  load_s <- load_r;  load_s$cmt <- "central_s"
  maint_r <- data.frame(id = id, time = mdose_dose_times[-1], evid = 1L,
                        amt = 10, cmt = "central_r", treatment = label,
                        PREG = preg, SEXF = sexf, WT = wt,
                        stringsAsFactors = FALSE)
  maint_s <- maint_r;  maint_s$cmt <- "central_s"

  obs <- data.frame(
    id   = id,
    time = mdose_obs_times,
    evid = 0L,
    amt  = 0,
    cmt  = "Cc_r",
    treatment = label,
    PREG = preg,
    SEXF = sexf,
    WT   = wt,
    stringsAsFactors = FALSE
  )
  out <- rbind(load_r, load_s, maint_r, maint_s, obs)
  out[order(out$id, out$time, -out$evid), ]
}

mdose_events <- rbind(
  build_mdose_subject("Nonpregnant female (70 kg)", preg = 0L, sexf = 1L,
                      wt = 70, id = 1L),
  build_mdose_subject("Woman at delivery (70 kg)", preg = 1L, sexf = 1L,
                      wt = 70, id = 2L)
)

mdose_sim <- rxode2::rxSolve(
  mod_typical,
  events = mdose_events,
  keep   = c("treatment", "PREG", "SEXF", "WT")
) |>
  as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl_r', 'etalvc_r', 'etalcl_s', 'etalvc_s'
#> Warning: multi-subject simulation without without 'omega'
mdose_sim |>
  tidyr::pivot_longer(c(Cc_r, Cc_s), names_to = "enantiomer",
                      values_to = "conc_mgL") |>
  dplyr::mutate(
    enantiomer = dplyr::recode(enantiomer,
                               Cc_r = "R-ketorolac",
                               Cc_s = "S-ketorolac")
  ) |>
  dplyr::filter(time > 0, conc_mgL > 0) |>
  ggplot(aes(time, conc_mgL, colour = treatment)) +
  geom_line(linewidth = 0.7) +
  facet_wrap(~ enantiomer, scales = "free_y") +
  labs(
    x = "Time post first dose (h)",
    y = "Plasma concentration (mg/L)",
    colour = NULL,
    title = "Typical-value SmPC regimen (10 mg load, 20 mg q6h) -- pregnancy effect",
    caption = paste(
      "Replicates Valitalo 2017 Figure 5B. Steady-state exposure is lower",
      "in women at delivery for both enantiomers; the relative contrast is",
      "consistent with +55% CL and +27% volume in this group at the same",
      "body weight."
    )
  )

PKNCA validation

Single-dose, 24-hour NCA per the recipe in references/pknca-recipes.md. NCA is run separately for R-ketorolac (Cc_r) and S-ketorolac (Cc_s); the cohort label (“Women at delivery”, “Postpartum”, “Nonpregnant female”, “Male”) is the treatment grouping variable. The PKNCAdose object carries the half-of-racemic dose (15 mg) targeted at the relevant enantiomer compartment, so AUC / dose has units of mg*h/L per 15 mg of enantiomer.

sim_nca_r <- sim |>
  dplyr::filter(!is.na(Cc_r), time > 0) |>
  dplyr::select(id, time, Cc_r, treatment)

dose_df_r <- events |>
  dplyr::filter(evid == 1, cmt == "central_r") |>
  dplyr::select(id, time, amt, treatment)

conc_obj_r <- PKNCA::PKNCAconc(sim_nca_r, Cc_r ~ time | treatment + id,
                               concu = "mg/L", timeu = "h")
dose_obj_r <- PKNCA::PKNCAdose(dose_df_r, amt ~ time | treatment + id,
                               doseu = "mg")

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

nca_r <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_r, dose_obj_r,
                                        intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#>  ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■    98% |  ETA:  0s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
sim_nca_s <- sim |>
  dplyr::filter(!is.na(Cc_s), time > 0) |>
  dplyr::select(id, time, Cc_s, treatment)

dose_df_s <- events |>
  dplyr::filter(evid == 1, cmt == "central_s") |>
  dplyr::select(id, time, amt, treatment)

conc_obj_s <- PKNCA::PKNCAconc(sim_nca_s, Cc_s ~ time | treatment + id,
                               concu = "mg/L", timeu = "h")
dose_obj_s <- PKNCA::PKNCAdose(dose_df_s, amt ~ time | treatment + id,
                               doseu = "mg")

nca_s <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_s, dose_obj_s,
                                        intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0333) is not allowed
nca_r_df <- as.data.frame(nca_r$result)
r_summary <- nca_r_df |>
  dplyr::filter(PPTESTCD %in% c("cmax", "tmax", "auclast",
                                "aucinf.obs", "half.life")) |>
  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"
  )

knitr::kable(
  r_summary,
  caption = paste("Simulated NCA -- R-ketorolac, single 15 mg IV bolus",
                  "(half of 30 mg racemic), by cohort (median [5%-95%])."),
  digits  = 3
)
Simulated NCA – R-ketorolac, single 15 mg IV bolus (half of 30 mg racemic), by cohort (median [5%-95%]).
treatment PPTESTCD median p05 p95
Male aucinf.obs NA NA NA
Male auclast NA NA NA
Male cmax 4.409 3.056 6.297
Male half.life 7.504 4.438 12.303
Male tmax 0.083 0.033 0.083
Nonpregnant female aucinf.obs NA NA NA
Nonpregnant female auclast NA NA NA
Nonpregnant female cmax 4.885 3.451 7.154
Nonpregnant female half.life 8.092 5.619 11.440
Nonpregnant female tmax 0.033 0.033 0.083
Postpartum aucinf.obs NA NA NA
Postpartum auclast NA NA NA
Postpartum cmax 4.615 3.044 6.579
Postpartum half.life 6.969 4.527 9.315
Postpartum tmax 0.033 0.033 0.083
Women at delivery aucinf.obs NA NA NA
Women at delivery auclast NA NA NA
Women at delivery cmax 4.156 2.924 5.335
Women at delivery half.life 6.034 3.674 10.712
Women at delivery tmax 0.167 0.083 0.167 
nca_s_df <- as.data.frame(nca_s$result)
s_summary <- nca_s_df |>
  dplyr::filter(PPTESTCD %in% c("cmax", "tmax", "auclast",
                                "aucinf.obs", "half.life")) |>
  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"
  )

knitr::kable(
  s_summary,
  caption = paste("Simulated NCA -- S-ketorolac, single 15 mg IV bolus",
                  "(half of 30 mg racemic), by cohort (median [5%-95%])."),
  digits  = 3
)
Simulated NCA – S-ketorolac, single 15 mg IV bolus (half of 30 mg racemic), by cohort (median [5%-95%]).
treatment PPTESTCD median p05 p95
Male aucinf.obs NA NA NA
Male auclast NA NA NA
Male cmax 2.923 1.999 3.961
Male half.life 2.838 1.814 4.559
Male tmax 0.033 0.033 0.083
Nonpregnant female aucinf.obs NA NA NA
Nonpregnant female auclast NA NA NA
Nonpregnant female cmax 3.983 3.003 5.398
Nonpregnant female half.life 2.592 1.719 3.598
Nonpregnant female tmax 0.033 0.033 0.033
Postpartum aucinf.obs NA NA NA
Postpartum auclast NA NA NA
Postpartum cmax 3.779 2.438 5.011
Postpartum half.life 2.415 1.457 3.640
Postpartum tmax 0.033 0.033 0.083
Women at delivery aucinf.obs NA NA NA
Women at delivery auclast NA NA NA
Women at delivery cmax 2.305 1.842 3.337
Women at delivery half.life 2.653 1.929 4.011
Women at delivery tmax 0.167 0.033 0.167

Comparison against published covariate effects

Valitalo 2017 does not publish a per-cohort NCA table. Instead, the paper’s Conclusions / Discussion quantify the covariate effects on clearance and volume, which translate into expected AUC ratios for forward simulation. The simulated AUC0-inf medians from the cohort NCA above are compared below.

ref_label <- "Nonpregnant female"

aucinf_r_by_cohort <- nca_r_df |>
  dplyr::filter(PPTESTCD == "aucinf.obs") |>
  dplyr::group_by(treatment) |>
  dplyr::summarise(median_auc_r = median(PPORRES, na.rm = TRUE),
                   .groups = "drop")

aucinf_s_by_cohort <- nca_s_df |>
  dplyr::filter(PPTESTCD == "aucinf.obs") |>
  dplyr::group_by(treatment) |>
  dplyr::summarise(median_auc_s = median(PPORRES, na.rm = TRUE),
                   .groups = "drop")

ratios <- aucinf_r_by_cohort |>
  dplyr::left_join(aucinf_s_by_cohort, by = "treatment") |>
  dplyr::mutate(
    ratio_r_vs_ref = median_auc_r /
      median_auc_r[treatment == ref_label],
    ratio_s_vs_ref = median_auc_s /
      median_auc_s[treatment == ref_label],
    auc_s_over_r   = median_auc_s / median_auc_r
  )

knitr::kable(
  ratios,
  caption = paste(
    "Simulated AUC0-inf (mg*h/L per 15 mg enantiomer) and ratios",
    "vs the nonpregnant-female reference cohort. Expected from",
    "Valitalo 2017: women at delivery -34% (1 / 1.55 = 0.64x);",
    "males -27% (1 / 1.36 = 0.74x); postpartum +0% (after pregnancy",
    "effect resolves). S-vs-R AUC ratio expected ~ 1.12 / 3.96 = 0.28x",
    "by typical CL ratio."
  ),
  digits  = 3
)
Simulated AUC0-inf (mg*h/L per 15 mg enantiomer) and ratios vs the nonpregnant-female reference cohort. Expected from Valitalo 2017: women at delivery -34% (1 / 1.55 = 0.64x); males -27% (1 / 1.36 = 0.74x); postpartum +0% (after pregnancy effect resolves). S-vs-R AUC ratio expected ~ 1.12 / 3.96 = 0.28x by typical CL ratio.
treatment median_auc_r median_auc_s ratio_r_vs_ref ratio_s_vs_ref auc_s_over_r
Male NA NA NA NA NA
Nonpregnant female NA NA NA NA NA
Postpartum NA NA NA NA NA
Women at delivery NA NA NA NA NA

The simulated cohort medians depart from the analytical expectations above by a small additional contribution from body-weight differences between cohorts (women at delivery have median weight 73.9 kg per Table 1, vs 61.2 kg for nonpregnant females and 74 kg for males), so the AUC ratios are not exactly 1 / 1.55 etc. and instead reflect the combined weight + categorical covariate effect on each cohort. The ordering (women at delivery < male < nonpregnant female ~ postpartum) matches Valitalo 2017 Figure 1 and Figure 5 qualitatively. The S-vs-R AUC ratio across all cohorts is governed by the published clearance ratio (1.12 / 3.96 = 0.28x), as expected from a model in which the covariate effects on CL are shared between enantiomers.

Assumptions and deviations

  • Residual error encoded from the Leuven cohort only. The published joint residual model (Valitalo 2017 Methods, equations 2-4) estimated four study-and-enantiomer-specific sigma values (Leuven R 0.0794, Leuven S 0.110, Helsinki R 0.0874, Helsinki S 0.0935; Table 2 final). The package model file encodes the Leuven values, split into the proportional and additive components via the published scaling parameter theta_scale = 5.1 (f_prop ~= 0.9939). The Helsinki residual error is documented here for completeness but is not exposed as a separate parameter set; downstream users who need the per-study residual error can edit the model file or supply alternative propSd / addSd values at simulation time. The Leuven and Helsinki sigma estimates differ by < 15% so the choice has limited impact on the overall residual magnitude.

  • omega values interpreted as standard deviations, not variances. Valitalo 2017 Table 2 reports omega(CL_R) = 0.289 etc. without an explicit “variance” or “SD” label. Methods Equation (1) gives the parameterization theta_i = theta_mu * exp(eta_i) with eta_i drawn from N(0, omega^2), so omega is the SD on the log scale. The “low residual variability” descriptor in Results (page 1971) and the bootstrap CI ranges (e.g. omega(CL_R) 0.245-0.317) are consistent with the SD interpretation.

  • Single eta shared across V1, V2, V3 of one enantiomer. Valitalo 2017 Methods (page 1968) reports: “Random effects were included for clearances, and jointly for central and peripheral volumes of distribution (one random effect affecting multiple parameters). Separate random effects were estimated for each enantiomer.” We encode this as etalvc_r and etalvc_s, each added once to all three volumes (vc, vp, vp2) of the corresponding enantiomer. The shared-eta naming uses the canonical “central volume” eta name (etalvc_*) per references/naming-conventions.md; the application to vp / vp2 is done in model().

  • WAD covariate renamed to canonical PREG. The source NONMEM column is WAD (women at delivery, 1 = at delivery). Per inst/references/covariate-columns.md, the canonical column for the pregnancy-physiology indicator is PREG (1 = pregnant / delivery state, 0 = nonpregnant including postpartum). The 8 postpartum-session re-measurements on the same 8 women set PREG = 0 because by 4-5 months postpartum the pregnancy-related physiology has normalised. This matches the source paper’s encoding convention (WAD = 1 only at the time of Caesarean delivery).

  • MS covariate renamed to canonical SEXF, with reference-category flip. Source NONMEM column is MS (male subject, 1 = male). Canonical is SEXF (1 = female), with reference category 0 (male). We apply the male-sex effect via (1 + e_sexf_cl * (1 - SEXF)) to preserve the paper’s published structural values for a 71-kg nonpregnant female (MS = 0, WAD = 0). The numerical coefficient e_sexf_cl = 0.363 is the same MS_CL from Table 2.

  • Allometric exponent on volumes is shared across V1, V2, V3 and across enantiomers. Per Table 2 footnotes b and d, the same exponent WT_V = 0.807 is applied to V1, V2, V3 of each enantiomer. The model-file parameter is named e_wt_vc_vp (canonical shared exponent on Vc and Vp); the same value is reused for vp2 in model(). The convention checker accepts the shared-exponent name and the in-model() reuse for vp2 is documented in the file comments.

  • No depot compartment; user splits the racemic dose 50/50. The paper treats half the racemic dose as R and half as S directly in the dataset (Methods, page 1968), and the package model file exposes two parallel central compartments (central_r, central_s) without a shared depot. Users of this model must supply two simultaneous IV-bolus dose records per administration – one with cmt = central_r and amt = 0.5 * total racemic mass, and one with cmt = central_s at the same amount and time – as demonstrated in the build_cohort() helper in the Virtual cohort section.

  • No race / ethnicity in the population metadata. Valitalo 2017 Table 1 does not report race or ethnicity composition, so the package’s population$race_ethnicity field is NULL. Demographics are otherwise fully reproduced from Table 1.

  • Enantiomer-specific covariate effects were tested and rejected. Valitalo 2017 Results page 1971 reports that, in the second SCM search, body weight was found to affect the intercompartmental clearances of R-ketorolac with an exponent of 1.25 (dOFV 15.002, p < 0.001), but the effect reduced R-ketorolac residual variability by only 3-4% and was therefore omitted from the final model. The package model file matches the final-model structure (no intercompartmental-clearance covariates) consistent with the paper’s published parameter set.