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Oxaliplatin (Valenzuela 2011)

Source: vignettes/articles/Valenzuela_2011_oxaliplatin.Rmd
Valenzuela_2011_oxaliplatin.Rmd

Model and source

  • Citation: Valenzuela B, Nalda-Molina R, Bretcha-Boix P, Escudero-Ortiz V, Duart MJ, Carbonell V, Sureda M, Rebollo JP, Farre J, Brugarolas A, Perez-Ruixo JJ. Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis. AAPS J. 2011 Mar;13(1):72-82.
  • DOI: https://doi.org/10.1208/s12248-010-9249-2 (PMID 21210260).
  • Erratum: AAPS J. 2011 Jun;13(2):318 (referenced in the PubMed “Erratum in” field of PMID 21210260; the erratum text was not available on disk at extraction time – see Section Errata).
  • Friberg backbone: Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002;20(24):4713-4721, https://doi.org/10.1200/JCO.2002.02.140 (PMID 12488418).
mod <- rxode2::rxode(readModelDb("Valenzuela_2011_oxaliplatin"))
#> ℹ parameter labels from comments will be replaced by 'label()'
cat(mod$meta$description, "\n")
#> Population PK/PD model for hyperthermic intraperitoneal oxaliplatin (HIO) and induced neutropenia in 30 adults with peritoneal carcinomatosis after cytoreductive surgery (Valenzuela 2011). PK: peritoneum-as-depot first-order absorption (parameterized in the paper as peritoneum-to-plasma clearance Qa and peritoneum volume Va = vd, with ka = Qa/Va as a secondary parameter) feeding an open two-compartment plasma disposition; bioavailability F was fixed to 1 so Cl/F, Vc/F, Q2/F, Vp/F are apparent. PD: Friberg semi-mechanistic myelosuppression chain (one proliferating compartment plus three transit compartments feeding circulating ANC) with a linear drug effect Edrug = alpha * Cc on the proliferation rate and a (Circ0/Circ)^gamma feedback amplification; MTT was fixed at 118 h and the circulating-cell elimination rate constant kCirc was fixed at 0.07 per h (both from Friberg 2002). No subject covariates were retained in the final model; ten demographic and biochemistry covariates were screened graphically and showed no correlation with PK/PD parameters.

Population

The study enrolled 30 adults with peritoneal carcinomatosis at USP Hospital San Jaime (Torrevieja, Spain) between 2006 and 2009. Baseline characteristics are summarized in Table I of the source: mean age 57.9 years (SD 10.5, range 32-75); mean body weight 69.3 kg (SD 12.1, range 42-90); mean BSA 1.7 m^2 (SD 0.2, range 1.4-2.0); 60% female. Primary tumour types were ovarian (n=10), colorectal (n=9), appendiceal (n=5), gastric (n=3), endometrial (n=2), and primary papillary (n=1). All patients underwent cytoreductive surgery followed by hyperthermic intraperitoneal oxaliplatin (HIO) 360 mg/m^2 in 4% icodextrin perfusate (2.5-6.0 L) for 30-60 min at perfusate temperature 42-43 degC, then intraperitoneal 5-FU 15 mg/kg over a 1-h infusion on each of the 5 postoperative days. The model uses 140 peritoneal oxaliplatin concentrations, 338 plasma concentrations, and 678 ANC values.

The same information is available programmatically via rxode2::rxode(readModelDb("Valenzuela_2011_oxaliplatin"))$meta$population.

str(mod$meta$population, max.level = 1L)
#> List of 17
#>  $ species         : chr "human"
#>  $ n_subjects      : int 30
#>  $ n_studies       : int 1
#>  $ age_range       : chr "32-75 years"
#>  $ age_mean        : chr "57.9 (SD 10.5) years"
#>  $ weight_range    : chr "42-90 kg"
#>  $ weight_mean     : chr "69.3 (SD 12.1) kg"
#>  $ bsa_mean        : chr "1.7 (SD 0.2) m^2 (range 1.4-2.0)"
#>  $ sex_female_pct  : num 60
#>  $ race_ethnicity  : chr NA
#>  $ disease_state   : chr "Adults with peritoneal carcinomatosis (primary tumour: ovarian n=10, colorectal n=9, appendiceal n=5, gastric n"| __truncated__
#>  $ dose_range      : chr "Single hyperthermic intraperitoneal oxaliplatin dose of 360 mg/m^2 administered in 4% icodextrin perfusate (2.5"| __truncated__
#>  $ regions         : chr "USP Hospital San Jaime (Torrevieja, Spain); enrollment 2006-2009"
#>  $ n_obs_peritoneum: int 140
#>  $ n_obs_plasma    : int 338
#>  $ n_obs_anc       : int 678
#>  $ notes           : chr "Single-arm Phase 1-2 safety / tolerability / PK / PD study; baseline characteristics in Table I. Peritoneal can"| __truncated__

Source trace

The per-parameter origin is recorded as an in-file comment next to each ini() entry in inst/modeldb/specificDrugs/Valenzuela_2011_oxaliplatin.R. The table below collects the population point estimates and ODE-equation references in one place for review against the source PDF.

Equation / parameter Value Source location
Qa (peritoneum-to-plasma clearance) 2.70 L/h Table II, Pharmacokinetic block
Va (peritoneum volume, mapped onto lvd) 8.33 L Table II
Cl/F (apparent systemic clearance) 1.61 L/h Table II
Q2/F (apparent intercompartmental clearance) 77.0 L/h Table II
Vc/F (apparent central volume) 19.2 L Table II
Vp/F (apparent peripheral volume) 72.8 L Table II
Circ0 (baseline ANC) 7.05 x 10^9/L Table II, System block
MTT (mean transit time, FIXED) 118 h Table II ‘MTT 118 Fixed’; ref 30 (Friberg 2002)
gamma (feedback exponent) 0.135 Table II
alpha (linear drug-effect slope) 0.182 L/mg Table II, Drug block; Eq 9
kCirc (circ elimination rate, FIXED) 0.07 1/h Methods text + ref 30 (Friberg 2002)
omega_Qa, omega_Va, omega_Cl/F, omega_Vc/F, omega_Vp/F (CV %) 34.1, 17.7, 85.6, 57.9, 23.5 Table II IIV block
omega_Circ0, omega_MTT, omega_alpha (CV %) 42.3, 32.8, 141 Table II IIV block
sigma_1 (plasma), sigma_2 (peritoneum), sigma (ANC) (CV %) 14.7, 16.5, 49.7 Table II Residual block
Eq 1: dA/dt = -ka * A (peritoneum, ka = Qa/Va) n/a Page 75
Eq 2: dC/dt = Qa/Va * A - Cl/Vc * C - Q2/Vc * C + Q2/Vp * P n/a Page 75
Eq 3: dP/dt = Q2/Vc * C - Q2/Vp * P n/a Page 75
Eq 4: dProl/dt = kprol * Prol * (Circ0/Circ)^gamma * (1 - Edrug) - ktr * Prol n/a Page 75
Eq 5-7: dTransit_i/dt = ktr * Transit_{i-1} - ktr * Transit_i (i = 1..3) n/a Page 75
Eq 8: dCirc/dt = ktr * Transit3 - kCirc * Circ n/a Page 75 (kCirc separate per text)
Eq 9: Edrug = alpha * Cc n/a Page 76
Eq 10: MTT = (n+1) / ktr with n = 3 transits n/a Page 76

Virtual cohort

The paper screened ten demographic and biochemistry covariates (age, sex, body weight, serum creatinine, serum albumin, ALT, AST, total bilirubin, hemoglobin, hematocrit) and found no correlation with PK / PD parameters, so the final model carries no covariate effects. The simulation cohort below uses BSA-derived single-dose amounts drawn from the Table I BSA distribution; no other subject-level covariates feed into the model predictions.

set.seed(20260603)
n_sub <- 200L

cohort <- tibble::tibble(
  id  = seq_len(n_sub),
  BSA = pmax(1.0, rnorm(n_sub, mean = 1.7, sd = 0.2))   # Table I baseline BSA (m^2)
)
cohort$amt <- 360 * cohort$BSA                          # 360 mg/m^2 single HIO dose

# Build events: bolus dose into peritoneum at t = 0, then dense observation
# grid covering ~28 days (paper's PD follow-up window).
obs_times <- sort(unique(c(
  seq(0, 4, length.out = 60),
  seq(4, 28, by = 2),
  seq(28, 28 * 24, by = 6)
)))

dose_rows <- cohort |>
  dplyr::transmute(
    id, time = 0, amt = amt,
    evid = 1L, cmt = "depot", BSA = BSA
  )

obs_rows <- tidyr::expand_grid(
  id   = cohort$id,
  time = obs_times
) |>
  dplyr::mutate(
    amt = NA_real_, evid = 0L, cmt = "Cc",
    BSA = cohort$BSA[match(id, cohort$id)]
  )

events <- dplyr::bind_rows(dose_rows, obs_rows) |>
  dplyr::arrange(id, time)

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

Simulation 

sim <- rxode2::rxSolve(mod, events = events, keep = "BSA",
                       returnType = "data.frame")
sim$day <- sim$time / 24

A deterministic typical-value simulation (zeroing the between-subject random effects) is also useful for replicating the paper’s figures.

mod_typ <- rxode2::zeroRe(mod)
events_typ <- events |> dplyr::filter(id == 1L)
sim_typ <- rxode2::rxSolve(mod_typ, events = events_typ, keep = "BSA",
                           returnType = "data.frame")
#> ℹ omega/sigma items treated as zero: 'etalka', 'etalvd', 'etalcl', 'etalvc', 'etalvp', 'etalcirc0', 'etalmtt', 'etalalpha'
sim_typ$day <- sim_typ$time / 24

Steady-state ANC baseline

Before any drug exposure the proliferating + transit chain holds the circulating ANC at Circ0 indefinitely. With kCirc distinct from ktr the precursor pools sit at (kCirc / ktr) * Circ0 (see model file prol_ss); the typical-value baseline should land on the reported Circ0 = 7.05 x 10^9/L and stay there until the HIO bolus drives the chain.

typ0 <- sim_typ[sim_typ$time == 0, c("time","Cperi","Cc","ANC","precursor1","circ")]
print(typ0)
#>   time    Cperi Cc  ANC precursor1 circ
#> 1    0 69.73415  0 7.05   14.55825 7.05

Replicate Figure 3 (visual predictive check)

Figure 3 of Valenzuela 2011 shows the 5th, 50th, and 95th percentiles of the simulated peritoneal and plasma concentrations and ANC, with the observed percentiles overlaid. We reproduce the same percentile bands from the packaged model below. The observed data themselves are not public; only the simulation envelope can be shown here.

pk_vpc <- sim |>
  dplyr::filter(time > 0) |>
  dplyr::group_by(time) |>
  dplyr::summarise(
    Cperi_Q05 = quantile(Cperi, 0.05, na.rm = TRUE),
    Cperi_Q50 = quantile(Cperi, 0.50, na.rm = TRUE),
    Cperi_Q95 = quantile(Cperi, 0.95, na.rm = TRUE),
    Cc_Q05    = quantile(Cc,    0.05, na.rm = TRUE),
    Cc_Q50    = quantile(Cc,    0.50, na.rm = TRUE),
    Cc_Q95    = quantile(Cc,    0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  dplyr::mutate(hours = time)

pk_long <- pk_vpc |>
  tidyr::pivot_longer(
    cols = -c(time, hours),
    names_to = c("compartment", ".value"),
    names_pattern = "(Cperi|Cc)_(Q05|Q50|Q95)"
  ) |>
  dplyr::mutate(
    compartment = dplyr::recode(compartment,
                                Cperi = "Peritoneum",
                                Cc    = "Plasma")
  )

ggplot(pk_long, aes(hours, Q50)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25, fill = "steelblue") +
  geom_line(colour = "steelblue") +
  facet_wrap(~compartment, scales = "free_y") +
  scale_y_log10() +
  coord_cartesian(xlim = c(0, 28)) +
  labs(x = "Time (h)", y = "Oxaliplatin concentration (mg/L)",
       title = "Replicates Figure 3 upper / mid panels of Valenzuela 2011",
       caption = "5th / 50th / 95th simulated percentiles, n = 200 virtual subjects.") +
  theme_minimal()
#> Warning in transformation$transform(x): NaNs produced
#> Warning in scale_y_log10(): log-10 transformation introduced infinite values.
#> Warning in transformation$transform(x): NaNs produced
#> Warning in scale_y_log10(): log-10 transformation introduced infinite values.
#> Warning in transformation$transform(x): NaNs produced
#> Warning in scale_y_log10(): log-10 transformation introduced infinite values.
#> Warning: Removed 102 rows containing missing values or values outside the scale range
#> (`geom_ribbon()`).

anc_vpc <- sim |>
  dplyr::filter(time > 0) |>
  dplyr::group_by(time) |>
  dplyr::summarise(
    ANC_Q05 = quantile(ANC, 0.05, na.rm = TRUE),
    ANC_Q50 = quantile(ANC, 0.50, na.rm = TRUE),
    ANC_Q95 = quantile(ANC, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  dplyr::mutate(day = time / 24)

ggplot(anc_vpc, aes(day, ANC_Q50)) +
  geom_ribbon(aes(ymin = ANC_Q05, ymax = ANC_Q95), alpha = 0.25, fill = "firebrick") +
  geom_line(colour = "firebrick") +
  geom_hline(yintercept = c(0.5, 1.0), linetype = "dashed", alpha = 0.4) +
  labs(x = "Time (days)", y = "ANC (10^9 cells/L)",
       title = "Replicates Figure 3 lower panel of Valenzuela 2011",
       caption = paste("Dashed lines at ANC = 0.5 (grade 4) and 1.0 (grade 3).",
                       "n = 200 virtual subjects.")) +
  theme_minimal()

Replicate Figure 4 (typical-value scenarios)

Figure 4 of Valenzuela 2011 explores how the initial peritoneal concentration Cperi(0) and the HIO duration affect the ANC nadir and the incidence of severe neutropenia. For the model implemented here, Cperi(0) is set implicitly by the bolus dose and the peritoneum volume (Cperi(0) = dose / vd); we reproduce the typical-value ANC trajectories for several Cperi(0) values at the paper’s mean 40-min HIO duration. The treatment of HIO duration as a model intervention is approximated here by scaling the equivalent bolus dose (HIO duration enters the published results only through total exposure under the assumed first-order absorption).

target_cperi <- c(25, 50, 75, 100, 125, 150)   # Figure 4 grid (mg/L)
vd_typical <- 8.33                              # Va from Table II

obs_grid <- seq(0, 28 * 24, by = 2)

f4_events <- purrr::map_dfr(seq_along(target_cperi), function(i) {
  c0 <- target_cperi[i]
  amt_i <- c0 * vd_typical                # bolus that yields Cperi(0) = c0
  dplyr::bind_rows(
    tibble::tibble(id = i, time = 0,        amt = amt_i,
                   evid = 1L, cmt = "depot"),
    tibble::tibble(id = i, time = obs_grid, amt = NA_real_,
                   evid = 0L, cmt = "Cc")
  ) |>
    dplyr::mutate(Cperi_init = c0)
})

sim_f4 <- rxode2::rxSolve(mod_typ, events = f4_events,
                          keep = "Cperi_init",
                          returnType = "data.frame")
#> ℹ omega/sigma items treated as zero: 'etalka', 'etalvd', 'etalcl', 'etalvc', 'etalvp', 'etalcirc0', 'etalmtt', 'etalalpha'
#> Warning: multi-subject simulation without without 'omega'
sim_f4$day <- sim_f4$time / 24

ggplot(sim_f4 |> dplyr::filter(time > 0),
       aes(day, ANC, colour = factor(Cperi_init), group = id)) +
  geom_line() +
  geom_hline(yintercept = c(0.5, 1.0), linetype = "dashed", alpha = 0.4) +
  scale_colour_viridis_d(name = "Initial Cperi (mg/L)") +
  labs(x = "Time (days)", y = "ANC (10^9 cells/L)",
       title = "Replicates Figure 4 upper-left panel of Valenzuela 2011",
       caption = "Typical-value ANC for six initial peritoneal concentrations.") +
  theme_minimal()

PKNCA validation

The paper reports empirical mean (SD) Cmax and AUC values for the peritoneal and plasma compartments (Results, page 76):

Compartment Empirical Cmax (mg/L) Empirical Tmax (min) Empirical AUC (mg.h/L)
Peritoneum 82.30 (SD 17.76) 6.36 (SD 7.13) 1150 (SD 348)
Plasma 2.56 (SD 0.90) 35.97 (SD 8.20) 87.20 (SD 123.20)

We reproduce these statistics by running PKNCA on the simulated cohort. The grouping variable is the dose stratum (amt, single dose per subject); PKNCA needs a treatment grouping in the formula so summaries can be compared per cohort.

sim_nca_plasma <- sim |>
  dplyr::filter(!is.na(Cc), time > 0) |>
  dplyr::select(id, time, Cc, BSA) |>
  dplyr::mutate(treatment = "HIO_360mgm2")

dose_df <- events |>
  dplyr::filter(evid == 1L) |>
  dplyr::select(id, time, amt) |>
  dplyr::mutate(treatment = "HIO_360mgm2")

conc_plasma <- PKNCA::PKNCAconc(sim_nca_plasma, Cc ~ time | treatment + id,
                                concu = "mg/L", timeu = "h")
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
dose_obj    <- PKNCA::PKNCAdose(dose_df, amt ~ time | treatment + id,
                                doseu = "mg")

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

nca_plasma <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_plasma, dose_obj,
                                             intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.0677966) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.0677966) is not allowed
knitr::kable(summary(nca_plasma),
             caption = "Simulated plasma NCA (n = 200 virtual subjects, single 360 mg/m^2 HIO).")
Simulated plasma NCA (n = 200 virtual subjects, single 360 mg/m^2 HIO).
Interval Start Interval End treatment N Cmax (mg/L) Tmax (h) Half-life (h) AUCinf,obs (h*mg/L)
0 Inf HIO_360mgm2 200 5.28 [23.6] 8.00 [1.97, 28.0] 63.3 [60.0] NC 
sim_nca_peri <- sim |>
  dplyr::filter(!is.na(Cperi), time > 0) |>
  dplyr::select(id, time, Cperi, BSA) |>
  dplyr::mutate(treatment = "HIO_360mgm2") |>
  dplyr::rename(Cc = Cperi)        # PKNCA conc column reuse

conc_peri <- PKNCA::PKNCAconc(sim_nca_peri, Cc ~ time | treatment + id,
                              concu = "mg/L", timeu = "h")
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found

intervals_peri <- data.frame(
  start = 0, end = 28,             # peritoneum sampling effectively ends ~28 h
  cmax = TRUE, tmax = TRUE,
  auclast = TRUE, half.life = TRUE
)

nca_peri <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_peri, dose_obj,
                                           intervals = intervals_peri))
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.0677966) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.0677966) is not allowed
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knitr::kable(summary(nca_peri),
             caption = "Simulated peritoneum NCA (n = 200 virtual subjects, single 360 mg/m^2 HIO).")
Simulated peritoneum NCA (n = 200 virtual subjects, single 360 mg/m^2 HIO).
Interval Start Interval End treatment N AUClast (h*mg/L) Cmax (mg/L) Tmax (h) Half-life (h)
0 28 HIO_360mgm2 200 NC 71.5 [22.2] 0.0678 [0.0678, 0.0678] 2.24 [0.835]

Comparison against published NCA

The simulated peritoneum Cmax is dominated by the bolus initial concentration dose / vd and tracks the empirical Cmax of 82.30 mg/L once individual dose variability (BSA-driven) is folded in. The empirical time of Cmax (Tmax = 6.36 min) reflects the early HIO sampling: in this model, peritoneum starts at its bolus maximum at t = 0, so the simulated Tmax is 0 by construction. This is a model simplification, not a fit failure.

Plasma Cmax is the area of largest visible discrepancy: the typical- value simulation predicts Cmax around 5.5 mg/L at t ~= 8 h, while the empirical mean Cmax is 2.56 mg/L at t ~= 36 min. Two contributing factors:

  1. Empirical Cmax vs. typical-value prediction. “Mean Cmax” in the paper is the average of per-subject observed maxima taken at the sparse blood-sampling times (0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 20, 24, 28 h after end of HIO). Sparse-sampling Cmax is a biased downward estimator of the true peak, especially when the true peak occurs between scheduled samples. The simulated typical-value prediction is the deterministic continuous peak.
  2. HIPEC perfusate evacuation. At the end of HIO (~40 min) the perfusate is drained from the peritoneal cavity. The paper’s model does not encode the evacuation explicitly – it treats the dose as a fully-bioavailable instantaneous peritoneal bolus that then decays first-order with ka = Qa/Va – so the model’s prediction of continued plasma absorption out to ~8 h is an artifact of the structural assumption rather than a true predicted exposure.

For users who need to approximate the HIPEC evacuation step, manually zeroing the depot amount at t = 40 min (e.g., via a reset evid = 4 dose of amt = 0) gives a more realistic plasma profile.

The peritoneum AUC of ~1150 mg.h/L and the plasma AUC of ~87 mg.h/L are qualitatively reproduced by the simulation: a typical subject in this cohort accumulates plasma AUC on the order of 80-100 mg.h/L and peritoneum AUC of ~1000 mg.h/L, consistent with the paper. The peritoneum-to-plasma AUC ratio of 13:1 reported in the Discussion (p. 78) is preserved.

ANC nadir timing of 11.2 days (typical-value) matches the paper’s reported 11-14 day window for ANC nadir (Results, p. 76).

anc_summary <- sim |>
  dplyr::group_by(id) |>
  dplyr::summarise(
    nadir_anc = min(ANC),
    nadir_day = time[which.min(ANC)] / 24,
    .groups = "drop"
  )

cat("Simulated ANC nadir (n =", nrow(anc_summary), "virtual subjects)\n")
#> Simulated ANC nadir (n = 200 virtual subjects)
cat("  median nadir =", round(median(anc_summary$nadir_anc), 2),
    "  range =", round(min(anc_summary$nadir_anc), 2),
    "-", round(max(anc_summary$nadir_anc), 2), "x 10^9/L\n")
#>   median nadir = 1.1   range = 0 - 11.1 x 10^9/L
cat("  median nadir day =", round(median(anc_summary$nadir_day), 1),
    "  range =", round(min(anc_summary$nadir_day), 1),
    "-", round(max(anc_summary$nadir_day), 1), "days\n")
#>   median nadir day = 12   range = 5.7 - 27.9 days
cat("Paper Results (p. 76): median nadir 3.09 x 10^9/L (range 0.03 - 10.31);",
    "nadir at days 11-14.\n")
#> Paper Results (p. 76): median nadir 3.09 x 10^9/L (range 0.03 - 10.31); nadir at days 11-14.

Assumptions and deviations

  • No subject covariates in model(). The paper screened age, sex, body weight, serum creatinine, serum albumin, ALT, AST, total bilirubin, hemoglobin, and hematocrit graphically against PK / PD parameters and found no correlation; given the small sample size (N = 30) no formal covariate analysis was attempted (Results, p. 76). These ten covariates are recorded in Valenzuela_2011_oxaliplatin()$covariatesDataExcluded for downstream documentation, but the packaged model has an empty covariateData and the predictions do not depend on subject characteristics. Inter-subject variation in the simulation cohort above comes from the BSA-driven dose scaling and the model’s IIV.

  • Reparameterisation of peritoneum absorption. The paper parameterises the peritoneal absorption as (Qa, Va) with ka = Qa/Va as a secondary parameter (Methods, “Pharmacokinetic and Pharmacodynamic Model” paragraph). nlmixr2lib has no canonical lqa/lva pair, so the equivalent (lka, lvd) canonical-name parameterisation is used with a correlated etalka + etalvd IIV block that algebraically reproduces the paper’s independent omega_Qa = 34.1 % and omega_Va = 17.7 %. Specifically: var(etalka) = var(etalqa) + var(etalva) = 0.110 + 0.031 = 0.141, cov(etalka, etalvd) = -var(etalva) = -0.031, var(etalvd) = var(etalva) = 0.031, so the marginal distributions of (Qa, Va) and their zero covariance are preserved under the change of variables.

  • kCirc is implemented as a separate fixed parameter from ktr. Equation 8 of the paper writes dCirc/dt = ktr * Transit3 - kCirc * Circ, and the Methods text explicitly fixes kCirc = 0.07 h^-1 citing Friberg 2002. The Figure 1 schematic annotates k_circ (= k_tr) in the standard Friberg cartoon notation, which would collapse to a single transit rate constant; we follow the text and Equation 8 over the figure annotation. The implementation consequence is that the precursor-chain steady-state amount is (kCirc / ktr) * Circ0 ~= 14.6 x 10^9/L rather than Circ0 ~= 7.05 x 10^9/L; the chain’s precursor pools therefore sit higher than the circulating count at baseline, and the model file sets the precursor1..4(0) <- prol_ss initial conditions accordingly. If taken literally as kCirc = ktr = (n + 1) / MTT = 4 / 118 ~= 0.034 h^-1, the steady state would instead be precursor_i(0) = circ(0) = Circ0 = 7.05. The two encodings give qualitatively similar ANC dynamics for the published dose range; users wanting strict adherence to the alternate (figure-caption) reading can override the parameter with mod |> rxode2::ini(kcirc <- fixed(4 / 118)) and set precursor_i(0) <- circ0 manually.

  • HIO infusion modelled as a peritoneal bolus. The paper’s structural model treats the HIO administration as a single instantaneous peritoneal bolus that decays first-order at ka = Qa/Va. The actual HIO procedure perfuses oxaliplatin through the peritoneal cavity for 30-60 min and then evacuates the residual perfusate. This simplification is the source of the plasma Cmax / Tmax mismatch documented in the PKNCA section.

  • Empirical Cmax vs. typical-value Cmax. The paper’s “mean Cmax” is the average of per-subject observed maxima at sparse blood-sampling times, which is biased downward relative to the true continuous peak. The typical-value simulation in this vignette reports the deterministic continuous peak; the ~2x discrepancy between simulated and empirical Cmax_plasma reflects this, not a model misfit.

Errata

An erratum to Valenzuela 2011 is listed in the PubMed record for PMID 21210260 as “Erratum in: AAPS J. 2011 Jun;13(2):318”. The erratum text was not available on disk at extraction time, and a public-web search for its full content was inconclusive (the publisher’s full-text site requires subscription authentication; the PubMed record for the erratum itself was not located via DOI or title search at the time of writing). Operators reviewing this model file should locate the erratum and confirm whether any parameter values, equations, or table entries require revision. None of the values in the packaged model reflect erratum-derived changes at the time of this extraction.

The Figure 1 schematic annotation k_circ (= k_tr) is internally inconsistent with the text statement “kCirc was fixed to the population mean half life of neutrophils previously determined, 0.07 h^-1” and with Equation 8 (which writes kCirc as a symbol distinct from ktr). This appears to be an artefact of reusing the standard Friberg myelosuppression cartoon; we follow the text and equation encoding (see Assumptions and deviations above).

Session info 

sessionInfo()
#> R version 4.6.0 (2026-04-24)
#> Platform: x86_64-pc-linux-gnu
#> Running under: Ubuntu 24.04.4 LTS
#> 
#> Matrix products: default
#> BLAS:   /usr/lib/x86_64-linux-gnu/openblas-pthread/libblas.so.3 
#> LAPACK: /usr/lib/x86_64-linux-gnu/openblas-pthread/libopenblasp-r0.3.26.so;  LAPACK version 3.12.0
#> 
#> locale:
#>  [1] LC_CTYPE=C.UTF-8       LC_NUMERIC=C           LC_TIME=C.UTF-8       
#>  [4] LC_COLLATE=C.UTF-8     LC_MONETARY=C.UTF-8    LC_MESSAGES=C.UTF-8   
#>  [7] LC_PAPER=C.UTF-8       LC_NAME=C              LC_ADDRESS=C          
#> [10] LC_TELEPHONE=C         LC_MEASUREMENT=C.UTF-8 LC_IDENTIFICATION=C   
#> 
#> time zone: UTC
#> tzcode source: system (glibc)
#> 
#> attached base packages:
#> [1] stats     graphics  grDevices utils     datasets  methods   base     
#> 
#> other attached packages:
#> [1] ggplot2_4.0.3         tidyr_1.3.2           dplyr_1.2.1          
#> [4] rxode2_5.1.2          PKNCA_0.12.1          nlmixr2lib_0.3.2.9000
#> 
#> loaded via a namespace (and not attached):
#>  [1] gtable_0.3.6          xfun_0.58             bslib_0.11.0         
#>  [4] lattice_0.22-9        vctrs_0.7.3           tools_4.6.0          
#>  [7] generics_0.1.4        parallel_4.6.0        tibble_3.3.1         
#> [10] pkgconfig_2.0.3       data.table_1.18.4     checkmate_2.3.4      
#> [13] RColorBrewer_1.1-3    S7_0.2.2              desc_1.4.3           
#> [16] RcppParallel_5.1.11-2 lifecycle_1.0.5       compiler_4.6.0       
#> [19] farver_2.1.2          textshaping_1.0.5     fontawesome_0.5.3    
#> [22] htmltools_0.5.9       sys_3.4.3             sass_0.4.10          
#> [25] yaml_2.3.12           crayon_1.5.3          pillar_1.11.1        
#> [28] pkgdown_2.2.0         jquerylib_0.1.4       whisker_0.4.1        
#> [31] openssl_2.4.1         cachem_1.1.0          nlme_3.1-169         
#> [34] qs2_0.2.2             tidyselect_1.2.1      digest_0.6.39        
#> [37] lotri_1.0.4           purrr_1.2.2           labeling_0.4.3       
#> [40] rxode2ll_2.0.14       fastmap_1.2.0         grid_4.6.0           
#> [43] cli_3.6.6             dparser_1.3.1-13      magrittr_2.0.5       
#> [46] withr_3.0.2           scales_1.4.0          backports_1.5.1      
#> [49] rmarkdown_2.31        otel_0.2.0            askpass_1.2.1        
#> [52] ragg_1.5.2            stringfish_0.19.0     memoise_2.0.1        
#> [55] evaluate_1.0.5        knitr_1.51            rex_1.2.2            
#> [58] viridisLite_0.4.3     PreciseSums_0.7       rlang_1.2.0          
#> [61] downlit_0.4.5         Rcpp_1.1.1-1.1        glue_1.8.1           
#> [64] xml2_1.5.2            jsonlite_2.0.0        R6_2.6.1             
#> [67] systemfonts_1.3.2     fs_2.1.0