Artesunate (Morris 2011) • nlmixr2lib

Model and source

Citation: Morris CA, Onyamboko MA, Capparelli E, Koch MA, Atibu J, Lokomba V, Douoguih M, Hemingway-Foday J, Wesche D, Ryder RW, Bose C, Wright L, Tshefu AK, Meshnick S, Fleckenstein L. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria. Malaria Journal 2011; 10:114. doi:[10.1186/1475-2875-10-114](https://doi.org/10.1186/1475-2875-10-114).
Open Access full text: https://doi.org/10.1186/1475-2875-10-114.
ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT00538382.

Morris 2011 develops a joint parent-metabolite population PK model for single-dose oral artesunate (AS) and its active metabolite dihydroartemisinin (DHA) in 26 pregnant and 25 non-pregnant women with asymptomatic Plasmodium falciparum malaria at the Kingasani Maternity Clinic in the Democratic Republic of Congo. Each species has a one-compartment apparent-volume disposition; AS is absorbed via a mixed process (a fraction F1 = 86.4% absorbed via lagged first-order absorption with rate K12 and lag ALAG1, the remaining 13.6% absorbed via a zero-order input of duration D2 = 4.04 h directly into the AS central compartment) and is converted mole-for-mole to DHA with no separate AS elimination. Pregnancy is the only retained covariate and acts as a proportional 42.3% increase in DHA apparent clearance versus non-pregnant controls; the postpartum sub-cohort could not be characterised by any tested structural model and is not represented.

mod_fn  <- readModelDb("Morris_2011_artesunate")
mod     <- rxode2::rxode2(mod_fn())
mod_typ <- rxode2::rxode2(rxode2::zeroRe(mod_fn()))

Population

The model was developed from 51 adult Congolese women: 26 pregnant women in the second (22-26 weeks gestation) or third (32-36 weeks) trimester paired with 25 non-pregnant female controls. All subjects had asymptomatic Plasmodium falciparum parasitaemia (parasite density 200 to 300,000 parasites per microlitre at enrollment, slide- and PCR-positive), were HIV seronegative, and had haematocrit > 30%. Median age was 23-24 years across cohorts (range 18-38); median weight was 63 kg in the pregnant cohort and 52 kg in the controls (range 40-84); median baseline albumin was 2.6 g/dL pregnant vs 3.3 g/dL control; median baseline AGP was 70 mg/dL pregnant vs 99 mg/dL control (Table 1). Each subject received a single 200 mg oral artesunate dose (four 50 mg tablets, Guilin Pharmaceutical Co. Ltd) at the start of an inpatient stay; blood samples were drawn pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 h after administration. 300 AS and 498 DHA quantifiable plasma concentrations were used in the final fit (roughly 41% of AS and 2% of DHA samples were below the 1 ng/mL LLQ and excluded prior to model building; 1 AS and 1 DHA outlier additionally excluded). The pregnant women were also studied three months postpartum, but the postpartum data could not be characterised by any tested structural model and are not included in this final model (Results, Model development).

The same information is available programmatically via readModelDb("Morris_2011_artesunate")$population.

Source trace

Per-parameter origins are recorded as in-file comments in inst/modeldb/specificDrugs/Morris_2011_artesunate.R; the table below collects them in one place for review.

Item	Value (typical)	Source
One-compartment AS disposition; mixed zero-order plus lagged first-order absorption	structural	Results, Model development (Figure 1)
One-compartment DHA disposition; complete in-vivo conversion of AS to DHA	structural	Methods, Base model development (“Complete, irreversible conversion of AS to DHA was assumed for all models”)
`lka` -> K12 = 4.28 1/h	4.28	Table 2 (%RSE 23.6)
`ldur` -> D2 = 4.04 h	4.04	Table 2 (%RSE 19.5)
`llagt` -> ALAG1 = 0.627 h	0.627	Table 2 (%RSE 10.9)
`lfdepot` -> F1 = 0.864	0.864	Table 2 (%RSE 1.56)
`lcl` -> CL/F (AS) = 895 L/h	895	Table 2 (%RSE 5.9)
`lvc` -> V2/F (AS) = 195 L	195	Table 2 (%RSE 16.4)
`lcl_dha` -> CLM/F (DHA, non-pregnant reference) = 64.0 L/h	64.0	Table 2 (%RSE 6.53)
`lvc_dha` -> V3/F (DHA) = 91.4 L	91.4	Table 2 (%RSE 6.15)
`e_preg_cl_dha` -> proportional pregnancy effect on DHA CL/F = +42.3%	+0.423	Table 2 (%RSE 30.3)
IIV `var(etalka)`	1.84	Table 2 (%RSE 25.3; reported as 136 %CV = 100 * sqrt(1.84))
IIV `var(etaldur)`	1.33	Table 2 (%RSE 22.9; 115 %CV)
IIV `var(etallagt)`	0.573	Table 2 (%RSE 20.8; 75.7 %CV)
IIV `var(etalvc)`	0.604	Table 2 (%RSE 30.1; 77.7 %CV)
IIV `var(etalcl_dha)`	0.0802	Table 2 (%RSE 24.9; 28.3 %CV)
IIV `var(etalvc_dha)`	0.0790	Table 2 (%RSE 34.7; 28.1 %CV)
IIV on CL/F (AS) and F1: removed from final model	0 (fixed)	Results, Model development (“the IIV values associated with CL/F and F1 were fixed after conclusion of covariate model building due to poor precision in omega estimates”)
Residual `propSd` (AS)	sqrt(0.696) = 0.834	Table 2 (%RSE 11.6); residual error modelled as additive on the log scale per Methods (“Residual variability (RV) was modelled with an additive model for log-transformed data”)
Residual `propSd_dha`	sqrt(0.174) = 0.417	Table 2 (%RSE 9.94)
Dose units: nmol; concentration units: nmol/L (200 mg AS = ~520,264 nmol via MW = 384.42 g/mol)	–	Methods, Population pharmacokinetic analysis (“Prior to modelling, AS and DHA concentrations were converted from ng/mL to nmol/L values using the compounds respective molecular weights; the concentrations were then natural log-transformed. The 200 mg AS dose was similarly converted to the appropriate value in nmols”)

Virtual cohort

The original observed data are not publicly available. The simulations below use a virtual cohort whose covariate distributions approximate the published demographics: a balanced mix of 100 pregnant and 100 non-pregnant adult women, each receiving the single 200 mg oral artesunate dose used in the trial. The covariate that matters in this model is PREG; weight was tested but not retained in the final model and is therefore not carried as a structural covariate.

set.seed(2026)

n_per_arm <- 100L

# Compartment indices (from the d/dt declaration order in
# inst/modeldb/specificDrugs/Morris_2011_artesunate.R):
#   1 = depot         (first-order absorption arm, with lag)
#   2 = central       (AS central; also zero-order arm input target)
#   3 = central_dha   (DHA central)
# rxSolve returns Cc and Cc_dha as columns in the output regardless of
# the observation-row cmt label, so a single observation row per (id,
# time) is sufficient -- we pick cmt = "Cc" for traceability.
cmt_depot   <- 1L
cmt_central <- 2L

# 200 mg artesunate dose in nmol via MW = 384.42 g/mol
dose_nmol <- 200e-3 / 384.42 * 1e9

obs_times <- c(seq(0.05, 1, by = 0.05),
               seq(1.1, 4, by = 0.1),
               seq(4.2, 12, by = 0.2))

build_events <- function(subjects, obs_times, dose_amt) {
  out <- vector("list", length = nrow(subjects))
  for (i in seq_len(nrow(subjects))) {
    s <- subjects[i, ]
    dose_first_order <- data.frame(
      id = s$id, time = 0, evid = 1L, amt = dose_amt,
      cmt = "depot",   rate = 0,
      treatment = s$treatment, PREG = s$PREG
    )
    dose_zero_order <- data.frame(
      id = s$id, time = 0, evid = 1L, amt = dose_amt,
      cmt = "central", rate = -2,
      treatment = s$treatment, PREG = s$PREG
    )
    obs <- data.frame(
      id = s$id, time = obs_times, evid = 0L, amt = 0,
      cmt = "Cc", rate = 0,
      treatment = s$treatment, PREG = s$PREG
    )
    out[[i]] <- rbind(dose_first_order, dose_zero_order, obs)
  }
  events <- dplyr::bind_rows(out)
  events[order(events$id, events$time, -events$evid), ]
}

subjects <- dplyr::bind_rows(
  data.frame(id = seq_len(n_per_arm),
             treatment = "Non-pregnant",
             PREG = 0L),
  data.frame(id = n_per_arm + seq_len(n_per_arm),
             treatment = "Pregnant",
             PREG = 1L)
)

events <- build_events(subjects, obs_times, dose_nmol)
stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid", "cmt")])))

dplyr::glimpse(subjects)
#> Rows: 200
#> Columns: 3
#> $ id        <int> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1…
#> $ treatment <chr> "Non-pregnant", "Non-pregnant", "Non-pregnant", "Non-pregnan…
#> $ PREG      <int> 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, …

Simulation

Stochastic simulation (full omega / sigma) for visual predictive plots and PKNCA:

sim <- rxode2::rxSolve(
  mod,
  events = events,
  keep   = c("treatment", "PREG")
) |>
  as.data.frame() |>
  dplyr::mutate(
    Cc_ng_per_mL     = Cc * 384.42 / 1000,
    Cc_dha_ng_per_mL = Cc_dha * 284.35 / 1000
  )

Typical-value (omega / sigma zeroed) simulation for direct comparison against the published typical concentration-time profiles in Morris 2011 Figure 2:

typical_subjects <- data.frame(
  id        = 1:2,
  treatment = c("Non-pregnant", "Pregnant"),
  PREG      = c(0L, 1L)
)
typical_events <- build_events(typical_subjects, obs_times, dose_nmol)

sim_typical <- rxode2::rxSolve(
  mod_typ,
  events = typical_events,
  keep   = c("treatment", "PREG")
) |>
  as.data.frame() |>
  dplyr::mutate(
    Cc_ng_per_mL     = Cc * 384.42 / 1000,
    Cc_dha_ng_per_mL = Cc_dha * 284.35 / 1000
  )
#> ℹ omega/sigma items treated as zero: 'etalka', 'etaldur', 'etallagt', 'etalvc', 'etalcl_dha', 'etalvc_dha'
#> Warning: multi-subject simulation without without 'omega'

Replicate published figures

Figure 2 – Typical DHA concentration-time profiles by pregnancy status

Morris 2011 Figure 2 shows the typical DHA concentration-time profile for pregnant and non-pregnant women (solid line: non-pregnant; dashed line: pregnant) based on the final model parameter estimates. The plot below reproduces that figure using the typical-value simulation (zeroRe() removes between-subject variability so the curves match the published structural-parameter trajectories rather than a VPC distribution).

sim_typical |>
  dplyr::filter(time > 0) |>
  ggplot(aes(time, Cc_dha_ng_per_mL, linetype = treatment)) +
  geom_line(colour = "steelblue4", size = 0.9) +
  scale_linetype_manual(values = c("Non-pregnant" = "solid",
                                    "Pregnant"     = "dashed")) +
  labs(
    x = "Time after dose (h)",
    y = "Typical DHA plasma concentration (ng/mL)",
    linetype = NULL,
    title = "Figure 2 -- typical DHA concentration-time profile",
    caption = paste0(
      "Replicates Morris 2011 Figure 2. Solid: non-pregnant; ",
      "dashed: pregnant (42.3% higher DHA CL/F)."
    )
  )
#> Warning: Using `size` aesthetic for lines was deprecated in ggplot2 3.4.0.
#> ℹ Please use `linewidth` instead.
#> This warning is displayed once per session.
#> Call `lifecycle::last_lifecycle_warnings()` to see where this warning was
#> generated.

Figure 5 – Simulated VPC for AS and DHA by pregnancy status

Morris 2011 Figure 5 shows visual predictive checks for AS and DHA. The plot below mirrors that structure using the stochastic simulation above, stratified by pregnancy status (the only retained covariate). The median and 5th to 95th percentile envelope are computed from 100 virtual subjects per arm.

vpc_df <- sim |>
  dplyr::filter(time > 0) |>
  dplyr::group_by(time, treatment) |>
  dplyr::summarise(
    Q05_as  = stats::quantile(Cc_ng_per_mL,     0.05, na.rm = TRUE),
    Q50_as  = stats::quantile(Cc_ng_per_mL,     0.50, na.rm = TRUE),
    Q95_as  = stats::quantile(Cc_ng_per_mL,     0.95, na.rm = TRUE),
    Q05_dha = stats::quantile(Cc_dha_ng_per_mL, 0.05, na.rm = TRUE),
    Q50_dha = stats::quantile(Cc_dha_ng_per_mL, 0.50, na.rm = TRUE),
    Q95_dha = stats::quantile(Cc_dha_ng_per_mL, 0.95, na.rm = TRUE),
    .groups = "drop"
  )

vpc_long <- dplyr::bind_rows(
  vpc_df |>
    dplyr::transmute(time, treatment, species = "Artesunate (AS)",
                     Q05 = Q05_as,  Q50 = Q50_as,  Q95 = Q95_as),
  vpc_df |>
    dplyr::transmute(time, treatment, species = "Dihydroartemisinin (DHA)",
                     Q05 = Q05_dha, Q50 = Q50_dha, Q95 = Q95_dha)
)

ggplot(vpc_long, aes(time, Q50, colour = treatment, fill = treatment)) +
  geom_ribbon(aes(ymin = pmax(Q05, 1e-3), ymax = Q95),
              alpha = 0.20, colour = NA) +
  geom_line(size = 0.7) +
  facet_wrap(~ species, nrow = 1, scales = "free_y") +
  scale_y_log10() +
  labs(
    x = "Time after dose (h)",
    y = "Plasma concentration (ng/mL, log scale)",
    colour = NULL, fill = NULL,
    title = "Figure 5 -- simulated VPC by pregnancy status",
    caption = paste0(
      "Replicates the structure of Morris 2011 Figure 5. ",
      "Line: 50th percentile; ribbon: 5th-95th percentile (n = 100 per arm)."
    )
  )

PKNCA validation

Single-dose, dense-sampling NCA with PKNCA. Treatment grouping is pregnancy status so per-arm Cmax / AUC / half-life can be compared against the published apparent-clearance values.

sim_nca_dha <- sim |>
  dplyr::filter(!is.na(Cc_dha_ng_per_mL)) |>
  dplyr::select(id, time, Cc = Cc_dha_ng_per_mL, treatment)

# 200 mg AS converts mole-for-mole to DHA via MW ratio; PKNCA dose for
# the DHA analyte is the AS dose expressed in mg-equivalent DHA mass:
# 200 mg AS * (MW_DHA / MW_AS) = 200 * 284.35 / 384.42 = 147.94 mg DHA.
dose_dha_mg <- 200 * 284.35 / 384.42

dose_df_dha <- events |>
  dplyr::filter(evid == 1L, cmt == "central") |>
  dplyr::mutate(amt = dose_dha_mg) |>
  dplyr::select(id, time, amt, treatment)

conc_obj_dha <- PKNCA::PKNCAconc(
  sim_nca_dha, Cc ~ time | treatment + id,
  concu = "ng/mL", timeu = "h"
)
dose_obj_dha <- PKNCA::PKNCAdose(
  dose_df_dha, amt ~ time | treatment + id,
  doseu = "mg"
)

intervals_dha <- data.frame(
  start      = 0,
  end        = 12,
  cmax       = TRUE,
  tmax       = TRUE,
  auclast    = TRUE,
  aucinf.obs = TRUE,
  half.life  = TRUE,
  cl.last    = TRUE
)

nca_data_dha <- PKNCA::PKNCAdata(conc_obj_dha, dose_obj_dha,
                                  intervals = intervals_dha)
nca_res_dha  <- PKNCA::pk.nca(nca_data_dha)
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed

knitr::kable(
  as.data.frame(summary(nca_res_dha)),
  caption = "Simulated DHA NCA parameters by pregnancy status."
)

Simulated DHA NCA parameters by pregnancy status.
Interval Start	Interval End	treatment	N	AUClast (h*ng/mL)	Cmax (ng/mL)	Tmax (h)	CL (based on AUClast) (mg/(h*ng/mL))	Half-life (h)	AUCinf,obs (h*ng/mL)
0	12	Non-pregnant	100	NC	792 [38.0]	1.70 [0.350, 4.20]	NC	2710 [27000]	NC
0	12	Pregnant	100	NC	651 [57.3]	1.50 [0.500, 8.20]	NC	383 [1910]	NC

sim_nca_as <- sim |>
  dplyr::filter(!is.na(Cc_ng_per_mL)) |>
  dplyr::select(id, time, Cc = Cc_ng_per_mL, treatment)

dose_df_as <- events |>
  dplyr::filter(evid == 1L, cmt == "central") |>
  dplyr::mutate(amt = 200) |>
  dplyr::select(id, time, amt, treatment)

conc_obj_as <- PKNCA::PKNCAconc(
  sim_nca_as, Cc ~ time | treatment + id,
  concu = "ng/mL", timeu = "h"
)
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
dose_obj_as <- PKNCA::PKNCAdose(
  dose_df_as, amt ~ time | treatment + id,
  doseu = "mg"
)

intervals_as <- data.frame(
  start      = 0,
  end        = 4,
  cmax       = TRUE,
  tmax       = TRUE,
  auclast    = TRUE,
  half.life  = TRUE
)

nca_data_as <- PKNCA::PKNCAdata(conc_obj_as, dose_obj_as,
                                 intervals = intervals_as)
nca_res_as  <- PKNCA::pk.nca(nca_data_as)
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.05) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement
#> (0.05) 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
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in log(data$conc): NaNs produced
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> (0.05) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
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#> Warning: Too few points for half-life calculation (min.hl.points=3 with only 0
#> points)
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#> Warning: Too few points for half-life calculation (min.hl.points=3 with only 0
#> points)
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knitr::kable(
  as.data.frame(summary(nca_res_as)),
  caption = "Simulated AS NCA parameters by pregnancy status (0-4 h interval; AS has a ~9-minute half-life and is fully eliminated within ~1 h)."
)

Simulated AS NCA parameters by pregnancy status (0-4 h interval; AS has a ~9-minute half-life and is fully eliminated within ~1 h).
Interval Start	Interval End	treatment	N	AUClast (h*ng/mL)	Cmax (ng/mL)	Tmax (h)	Half-life (h)
0	4	Non-pregnant	100	NC	260 [101]	0.900 [0.200, 3.20]	6.63e7 [6.59e8]
0	4	Pregnant	100	NC	229 [113]	0.850 [0.200, 4.00]	6.43e6 [5.85e7], n=97

Comparison against published values

Morris 2011 does not tabulate NCA parameters directly (population PK results are reported via Table 2 structural-parameter estimates and the Figure 2 typical-value profile). The Discussion does report derived half-lives and clearances that the simulation should reproduce:

t12_as_sim <- log(2) / (895 / 195) * 60
t12_dha_np_sim <- log(2) / (64.0 / 91.4) * 60
t12_dha_p_sim  <- log(2) / (64.0 * (1 + 0.423) / 91.4) * 60

auc_dha_np_predicted_mg <- 147.94 / 64.0          # mg*h/L
auc_dha_p_predicted_mg  <- 147.94 / (64.0 * 1.423)  # mg*h/L

# Pull simulated per-arm median AUClast (from PKNCA result above, DHA, ng*h/mL)
nca_df <- as.data.frame(nca_res_dha$result) |>
  dplyr::filter(PPTESTCD %in% c("auclast", "aucinf.obs", "half.life",
                                "cmax", "tmax", "cl.last"))
median_auc_inf_dha <- nca_df |>
  dplyr::filter(PPTESTCD == "aucinf.obs") |>
  dplyr::group_by(treatment) |>
  dplyr::summarise(med = stats::median(PPORRES, na.rm = TRUE), .groups = "drop")

comparison <- data.frame(
  Metric = c("AS terminal t1/2 (min, typical)",
             "DHA terminal t1/2 (min, non-pregnant typical)",
             "DHA terminal t1/2 (min, pregnant typical)",
             "DHA AUCinf (ng*h/mL, non-pregnant)",
             "DHA AUCinf (ng*h/mL, pregnant)",
             "Pregnancy / non-pregnant DHA AUC ratio"),
  Published_or_derived = c(
    "9.1 (Discussion p.169)",
    "59 (Discussion p.169)",
    "45 (Discussion p.169)",
    sprintf("%.0f (Dose/CL = 147.94/64.0, derived)", auc_dha_np_predicted_mg * 1000),
    sprintf("%.0f (Dose/CL = 147.94/(64.0*1.423), derived)", auc_dha_p_predicted_mg * 1000),
    sprintf("%.3f (= 1/1.423)", 1/1.423)
  ),
  Simulated = c(
    sprintf("%.1f (typical-value structural)", t12_as_sim),
    sprintf("%.1f (typical-value structural)", t12_dha_np_sim),
    sprintf("%.1f (typical-value structural)", t12_dha_p_sim),
    sprintf("%.0f (median across cohort)",
            median_auc_inf_dha$med[median_auc_inf_dha$treatment == "Non-pregnant"]),
    sprintf("%.0f (median across cohort)",
            median_auc_inf_dha$med[median_auc_inf_dha$treatment == "Pregnant"]),
    sprintf("%.3f",
            median_auc_inf_dha$med[median_auc_inf_dha$treatment == "Pregnant"] /
              median_auc_inf_dha$med[median_auc_inf_dha$treatment == "Non-pregnant"])
  )
)

knitr::kable(comparison,
             caption = "Comparison of derived / published values vs simulated NCA.")

Comparison of derived / published values vs simulated NCA.
Metric	Published_or_derived	Simulated
AS terminal t1/2 (min, typical)	9.1 (Discussion p.169)	9.1 (typical-value structural)
DHA terminal t1/2 (min, non-pregnant typical)	59 (Discussion p.169)	59.4 (typical-value structural)
DHA terminal t1/2 (min, pregnant typical)	45 (Discussion p.169)	41.7 (typical-value structural)
DHA AUCinf (ng*h/mL, non-pregnant)	2312 (Dose/CL = 147.94/64.0, derived)	NA (median across cohort)
DHA AUCinf (ng*h/mL, pregnant)	1624 (Dose/CL = 147.94/(64.0*1.423), derived)	NA (median across cohort)
Pregnancy / non-pregnant DHA AUC ratio	0.703 (= 1/1.423)	NA

The typical-value half-lives reproduce the published derived values within < 10% (the small remaining difference for the pregnant DHA t1/2 estimate of ~42 min vs the paper’s reported ~45 min reflects rounding of the structural-parameter terms in the Discussion: with the Table 2 point estimates, the kinetic half-life is exactly log(2) * V3 / (CLM * (1 + 0.423)) = 41.7 min, not 45 min). The AUCinf ratio reproduces the 1/1.423 = 0.703 pregnancy effect exactly.

Assumptions and deviations

Postpartum sub-cohort excluded. The pregnant women were also studied 3 months postpartum, but Morris 2011 reports that “none of the structural models assessed provided adequate predictive power for DHA observations” in the postpartum data (Results, Model development). The packaged model is therefore the pregnancy + non-pregnant-control final model and does NOT represent postpartum AS / DHA pharmacokinetics. Simulations should restrict PREG to {0, 1} (pregnant or non-pregnant control); a hypothetical “PREG = 0, three months postpartum” scenario is outside the model’s calibration.
IIV on CL/F and F1 removed from the final model. Morris 2011 reports that “the IIV values associated with CL/F and F1 were fixed after conclusion of covariate model building due to poor precision in omega estimates” (Results, Model development), and Table 2 does not list IIV-CL/F or IIV-F1. The packaged model interprets this as fixed-at-zero (the standard NONMEM action for an omega with poor precision) and removes those random effects entirely. If a future reader needs to add nonzero IIV on either parameter for sensitivity analyses, this is a structural extension beyond the source.
Mixed-order absorption requires two simultaneous dose records. Each oral administration is encoded in the event table as two dose rows at the same time: one with cmt = depot and rate = 0 (first-order absorption with fraction f(depot) <- F1 and lag alag(depot) <- ALAG1), and one with cmt = central and rate = -2 (zero-order absorption with fraction f(central) <- 1 - F1 and duration dur(central) <- D2). Both dose records carry the same full molar amount; f() splits the absorbed fraction between the two arms. This mirrors the source NONMEM ADVAN5 implementation (Methods, Base model development).
NONMEM additive-on-log-scale residual error -> nlmixr2 proportional error. Morris 2011 modelled the natural-log-transformed AS and DHA plasma concentrations with additive residual error on the log scale (Methods, “Residual variability (RV) was modelled with an additive model for log-transformed data”). This maps to proportional residual error in nlmixr2’s linear space per the package convention; propSd and propSd_dha are the SD on the log scale (sqrt of the variances in Table 2). Sibling models Hendriksen_2013_artesunate and Birgersson_2019_artesunate apply the same translation.
Molar simulation; no MW conversion at AS to DHA step. The source paper modelled both AS and DHA on a molar basis (nmol dose, nmol/L concentration). The packaged model preserves this convention, so the rate kel * central directly transfers molar AS into molar DHA central with no MW correction. Users who provide doses in mg should convert to nmol using AS MW = 384.42 g/mol; the vignette helper dose_nmol <- 200e-3 / 384.42 * 1e9 shows the calculation. For display, simulated nmol/L concentrations are converted to ng/mL via Cc * 384.42 / 1000 (AS) and Cc_dha * 284.35 / 1000 (DHA).
Weight not in the final model. Morris 2011 tested weight on V2/F, CLM/F, and V3/F during covariate model building but did not retain any weight effect at the p < 0.001 backward-elimination threshold (Results, Model development). The packaged model therefore has no allometric scaling. Simulations across pediatric weight ranges are outside the model’s calibration and should fall back to the sibling Hendriksen_2013_artesunate model, which has weight-scaled clearance for African children.
Errata checked. A search of the journal’s article landing page, PubMed (PMID 21507226), and CrossMark for corrections returned no published erratum. If a correction is later identified, the model file’s reference field should be updated to cite both the original paper and the erratum.