Meropenem (Themans 2019)
Source:vignettes/articles/Themans_2019_meropenem.Rmd
Themans_2019_meropenem.RmdModel and source
- Citation: Themans P, Winkin J J, Musuamba F T (2019). Towards a generic tool for prediction of meropenem systemic and infection-site exposure: a physiologically based pharmacokinetic model for adult patients with pneumonia. Drugs R D 19(4):339-355. doi:10.1007/s40268-019-0268-x. DDMORE Foundation Model Repository: DDMODEL00000301.
- Description: Three-compartment population PK model for meropenem in adults with severe pneumonia, with parallel ELF (epithelial lining fluid) sampling (Themans 2019), as packaged in DDMORE Foundation Model Repository entry DDMODEL00000301.
- DDMORE Foundation Model Repository entry:
DDMODEL00000301 - Article (per task metadata): https://doi.org/10.1007/s40268-019-0268-x
The DDMORE Model_Accomodations file describes the same body of work (same authors, drug, indication, scenario = 4) as a British Journal of Pharmacology submission dated July 2019. The published article in Drugs in R&D (DOI above) was used as the canonical citation; the publication PDF was not on disk so external cross-checks against published tables/figures were not possible. See the Errata section for how the .lst’s final estimates were used in lieu of a published parameter table, and how a unit convention in the source NONMEM model was reconciled against the simulated dataset shipped in the bundle.
Population
The model was fit to adult patients with severe pneumonia receiving
meropenem by IV infusion. Specific demographics (n, age, sex, race,
study sites) could not be cross-checked against the publication because
the article PDF was not on disk; the demographics of the bundle’s
Simulated_dataset.csv (60 simulated subjects) provide the
only on-disk reference and span body weight 45-128 kg (mean ~78 kg) and
raw measured GFR 19-401 mL/min. The wide GFR range covers severe renal
impairment through to augmented renal clearance, consistent with a
critically ill ICU pneumonia population.
The same information is available programmatically via the model’s
population metadata
(readModelDb("Themans_2019_meropenem")$population).
Source trace
The per-parameter origin is recorded as an in-file comment next to
each ini() entry in
inst/modeldb/ddmore/Themans_2019_meropenem.R. The table
below collects them in one place for review. Every THETA(*)
reference is to the FINAL PARAMETER ESTIMATE block of
Output_real_merop_PK_run3.lst (post
MINIMIZATION SUCCESSFUL, OBJV = 1488.719);
OMEGA and SIGMA references are to the
corresponding final blocks in the same listing.
| Equation / parameter | Value | Source location |
|---|---|---|
lcl (CL, L/h) |
log(7.94) |
DDMODEL00000301 .lst FINAL THETA(1) |
e_crcl_cl (CRCL exponent on CL) |
0.722 |
DDMODEL00000301 .lst FINAL THETA(2) |
lvc (V1, L) |
log(13.6) |
DDMODEL00000301 .lst FINAL THETA(3) |
e_wt_vc (WT exponent on V1) |
0.949 |
DDMODEL00000301 .lst FINAL THETA(4) |
lq (Q2, L/h) |
log(6.73) |
DDMODEL00000301 .lst FINAL THETA(5) |
lvp (V2, L) |
log(4.08) |
DDMODEL00000301 .lst FINAL THETA(6) |
lq2 (Q3, L/h) |
log(8.22) |
DDMODEL00000301 .lst FINAL THETA(7) |
lvp2 (V3, L) |
log(10.1) |
DDMODEL00000301 .lst FINAL THETA(8) |
e_wt_vp (WT exponent on V2) |
1.04 |
DDMODEL00000301 .lst FINAL THETA(9) |
lf_elf (ELF/V2 partition) |
log(0.249) |
DDMODEL00000301 .lst FINAL THETA(10) = 249, rescaled by 1/1000 to mg-consistent units (see Errata) |
etalcl variance |
0.126 |
DDMODEL00000301 .lst FINAL OMEGA ETA1 |
etalvc variance |
0.140 |
DDMODEL00000301 .lst FINAL OMEGA ETA2 |
etalvp variance |
1.76 |
DDMODEL00000301 .lst FINAL OMEGA ETA3 |
etalq2 variance |
0.187 |
DDMODEL00000301 .lst FINAL OMEGA ETA4 |
propSd (Cc proportional) |
sqrt(0.0240) |
DDMODEL00000301 .lst FINAL SIGMA EPS1 |
addSd (Cc additive, mg/L) |
sqrt(0.208) |
DDMODEL00000301 .lst FINAL SIGMA EPS2 |
propSd_Celf (Celf proportional) |
sqrt(0.404) |
DDMODEL00000301 .lst FINAL SIGMA EPS3 |
3-cmt ODE (d/dt(central) etc.) |
n/a | DDMODEL00000301 $SUBROUTINE ADVAN11 TRANS4 (.mod /
.lst) |
Plasma observation Cc = central / vc
|
n/a | DDMODEL00000301 $ERROR block:
Y = H1*(F*(1+EPS(1))+EPS(2)) for CMT == 1 |
ELF observation Celf = (peripheral1 / vp) * f_elf
|
n/a | DDMODEL00000301 $ERROR block:
Y = H2*(F*(1+EPS(3))) for CMT == 2; F = A2/S2, S2 =
V2/THETA(10) |
Virtual cohort
The bundle’s Simulated_dataset.csv ships a 60-subject
simulated cohort (1 g IV meropenem, 0.5 h infusion, q8h at steady state;
WT 45-128 kg, raw GFR 19-401 mL/min; one ELF observation per subject
within the dosing interval). The publication’s actual study population
demographics could not be reconstructed from the on-disk material; the
virtual cohort below mirrors the bundle’s covariate ranges.
set.seed(2019301L)
n_subj <- 200L
# Resample WT and CRCL (the source's GFR column, raw mL/min) from
# log-normal distributions with location-scale parameters chosen to
# reproduce the bundle's Simulated_dataset.csv summary statistics.
mu_wt <- log(78); sd_wt <- log(1.20) # ~78 kg, CV ~20%
mu_crcl <- log(80); sd_crcl <- log(1.85) # ~80 mL/min, broad CV (40-150 typical)
cohort <- tibble(
id = seq_len(n_subj),
WT = pmax(40, pmin(140, exp(rnorm(n_subj, mu_wt, sd_wt)))),
CRCL = pmax(15, pmin(420, exp(rnorm(n_subj, mu_crcl, sd_crcl))))
)
summary(cohort[, c("WT", "CRCL")])
#> WT CRCL
#> Min. : 48.37 Min. : 15.74
#> 1st Qu.: 67.50 1st Qu.: 49.26
#> Median : 76.72 Median : 73.73
#> Mean : 77.72 Mean : 95.56
#> 3rd Qu.: 86.34 3rd Qu.:122.18
#> Max. :119.75 Max. :420.00The simulation events: 1 g IV, 0.5 h infusion (RATE = 2000 mg/h), q8h
at steady state, with observations sampled densely over a single dosing
interval to support PKNCA. Plasma observations live on compartment
Cc (model compartment 4), ELF observations on
Celf (compartment 5).
obs_t <- c(seq(0, 1, by = 0.1), seq(1.5, 8, by = 0.5))
n_obs <- length(obs_t)
dose_rows <- cohort |>
transmute(id = id, time = 0, evid = 1L, amt = 1000, rate = 2000,
cmt = 1L, ss = 1L, ii = 8, WT = WT, CRCL = CRCL)
obs_rows <- cohort |>
tidyr::crossing(time = obs_t) |>
transmute(id = id, time = time, evid = 0L, amt = 0, rate = 0,
cmt = 4L, ss = 0L, ii = 0, WT = WT, CRCL = CRCL)
# A single observation row per (id, time) is sufficient because both Cc and
# Celf are computed algebraically every time the integrator stops; rxSolve
# returns both columns for every observation row regardless of `cmt`.
events <- dplyr::bind_rows(dose_rows, obs_rows) |>
dplyr::arrange(id, time, evid, cmt)Simulation
mod <- rxode2::rxode2(readModelDb("Themans_2019_meropenem"))
#> ℹ parameter labels from comments will be replaced by 'label()'
sim <- rxode2::rxSolve(
mod,
events = events,
keep = c("WT", "CRCL")
) |>
as.data.frame()
head(sim[, c("id", "time", "Cc", "Celf", "WT", "CRCL")])
#> id time Cc Celf WT CRCL
#> 1 1 0.0 1.463713 0.7682782 75.23055 134.6557
#> 2 1 0.1 12.488606 0.8178469 75.23055 134.6557
#> 3 1 0.2 21.610652 0.9858496 75.23055 134.6557
#> 4 1 0.3 29.225287 1.2461278 75.23055 134.6557
#> 5 1 0.4 35.642879 1.5780130 75.23055 134.6557
#> 6 1 0.5 41.107108 1.9651565 75.23055 134.6557For deterministic typical-value comparisons (no IIV), zero out the random effects:
mod_typ <- rxode2::zeroRe(mod)
sim_typ <- rxode2::rxSolve(mod_typ, events = events, keep = c("WT", "CRCL")) |>
as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalq2'
#> Warning: multi-subject simulation without without 'omega'Replicate observed behaviour
The publication PDF was not on disk, so the figures below are not direct figure-by-figure replications of the article. Instead they provide two kinds of sanity check:
- The simulated typical-value plasma trajectory at the bundle’s
reference covariates (
WT = 75,GFR = 65) reaches realistic meropenem plasma Cmax (~70-90 mg/L for 1 g over 0.5 h infusion) and decays with a multi-compartment profile. - The simulated typical-value ELF trajectory tracks plasma in shape
and at a dimensionally reasonable level (typical-value ELF / plasma
penetration of ~0.25 from the model’s
f_elf = 0.249partition factor, with kinetic delay due to distribution into the V2 / ELF compartment).
ref_events <- dplyr::bind_rows(
tibble(id = 1L, time = 0, evid = 1L, amt = 1000, rate = 2000,
cmt = 1L, ss = 1L, ii = 8, WT = 75, CRCL = 65),
tibble(id = 1L, time = obs_t, evid = 0L, amt = 0, rate = 0,
cmt = 4L, ss = 0L, ii = 0, WT = 75, CRCL = 65)
) |>
dplyr::arrange(id, time, evid, cmt)
ref_sim <- rxode2::rxSolve(mod_typ, events = ref_events) |> as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalq2'
ref_long <- ref_sim |>
dplyr::select(time, Cc, Celf) |>
dplyr::distinct() |>
tidyr::pivot_longer(c(Cc, Celf), names_to = "site", values_to = "conc") |>
dplyr::mutate(site = ifelse(site == "Cc", "Plasma (Cc)", "ELF (Celf)"))
ggplot(ref_long, aes(time, conc, colour = site)) +
geom_line(linewidth = 0.9) +
scale_y_log10() +
labs(x = "Time within dosing interval (h)",
y = "Concentration (mg/L)",
colour = NULL,
title = "Typical-value plasma and ELF trajectories at WT = 75 kg, GFR = 65 mL/min",
caption = "1 g meropenem IV q8h, 0.5 h infusion, steady state.")
Cross-check against the DDMORE simulated dataset
The bundle’s Simulated_dataset.csv contains 60 subjects
with one ELF observation per subject. The check below compares the
typical-value model prediction (no IIV) against the corresponding
observed DV value at each subject’s covariates and ELF observation time.
Differences are expected because the observed DV values carry
proportional residual error of ~64% CV (sqrt(0.404)), but
the typical-value-vs-observed scatter should be unbiased.
ds_path <- file.path("data", "Themans_2019_simulated.csv")
ddmore <- utils::read.csv(ds_path, stringsAsFactors = FALSE) |>
dplyr::rename(CRCL = GFR_valAbs)
elf_obs <- ddmore |>
dplyr::filter(CMT == 2, MDV == 0, EVID == 0)
# Build a single combined event table: one dose row per source ID at SS,
# plus one observation row per ELF observation in the bundle.
selfcheck_dose <- elf_obs |>
dplyr::distinct(ID, WT, CRCL) |>
dplyr::transmute(id = ID, time = 0, evid = 1L,
amt = 1000, rate = 2000, cmt = 1L,
ss = 1L, ii = 8, WT = WT, CRCL = CRCL)
selfcheck_obs <- elf_obs |>
dplyr::transmute(id = ID, time = TIME, evid = 0L,
amt = 0, rate = 0, cmt = 5L,
ss = 0L, ii = 0, WT = WT, CRCL = CRCL,
DV_observed = DV)
selfcheck_events <- dplyr::bind_rows(
selfcheck_dose |> dplyr::mutate(DV_observed = NA_real_),
selfcheck_obs
) |>
dplyr::arrange(id, time, evid)
selfcheck_sim <- rxode2::rxSolve(mod_typ,
events = selfcheck_events |>
dplyr::select(-DV_observed),
keep = c("WT", "CRCL")) |>
as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalq2'
#> Warning: multi-subject simulation without without 'omega'
# Pair each observed DV with the typical-value Celf at the same id/time.
matched <- selfcheck_obs |>
dplyr::inner_join(
selfcheck_sim |> dplyr::select(id, time, Celf),
by = c("id", "time")
)
ggplot(matched, aes(Celf, DV_observed)) +
geom_abline(slope = 1, intercept = 0, linetype = "dashed") +
geom_point(alpha = 0.7) +
scale_x_log10() + scale_y_log10() +
labs(x = "Model typical-value ELF (mg/L)",
y = "DDMORE Simulated_dataset.csv observed ELF DV (mg/L)",
title = "Bundle ELF DV vs model typical-value (no IIV)",
caption = "Dashed line = unity. Scatter is dominated by the proportional residual error (~64% CV).")
#> Warning in scale_y_log10(): log-10 transformation introduced
#> infinite values.
PKNCA validation
PKNCA is computed separately for plasma (Cc) and ELF
(Celf) over one dosing interval at steady state, using the
virtual cohort constructed earlier. The treatment grouping is a single
“meropenem 1 g q8h IV (SS)” stratum; per-cohort decomposition would
match the publication’s typical reporting style if the publication NCA
tables were available.
sim_nca_plasma <- sim |>
dplyr::filter(!is.na(Cc), time > 0) |>
dplyr::transmute(id = id, time = time, Cc = Cc,
treatment = "meropenem 1g q8h IV (SS)")
dose_df <- events |>
dplyr::filter(evid == 1L) |>
dplyr::transmute(id = id, time = time, amt = amt,
treatment = "meropenem 1g q8h IV (SS)")
conc_obj_plasma <- PKNCA::PKNCAconc(sim_nca_plasma, Cc ~ time | treatment + id,
concu = "mg/L", timeu = "hr")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | treatment + id,
doseu = "mg")
intervals_ss <- data.frame(
start = 0,
end = 8,
cmax = TRUE,
tmax = TRUE,
cmin = TRUE,
auclast = TRUE,
cav = TRUE
)
nca_plasma <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_plasma, dose_obj,
intervals = intervals_ss))
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#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
knitr::kable(summary(nca_plasma),
caption = "Plasma (Cc) NCA at steady state over the 0-8 h interval.")| Interval Start | Interval End | treatment | N | AUClast (hr*mg/L) | Cmax (mg/L) | Cmin (mg/L) | Tmax (hr) | Cav (mg/L) |
|---|---|---|---|---|---|---|---|---|
| 0 | 8 | meropenem 1g q8h IV (SS) | 200 | NC | 54.4 [32.0] | 3.37 [277] | 0.500 [0.500, 0.500] | NC |
sim_nca_elf <- sim |>
dplyr::filter(!is.na(Celf), time > 0) |>
dplyr::transmute(id = id, time = time, Celf = Celf,
treatment = "meropenem 1g q8h IV (SS)")
conc_obj_elf <- PKNCA::PKNCAconc(sim_nca_elf, Celf ~ time | treatment + id,
concu = "mg/L", timeu = "hr")
nca_elf <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_elf, dose_obj,
intervals = intervals_ss))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.1) is not allowed
knitr::kable(summary(nca_elf),
caption = "ELF (Celf) NCA at steady state over the 0-8 h interval.")| Interval Start | Interval End | treatment | N | AUClast (hr*mg/L) | Cmax (mg/L) | Cmin (mg/L) | Tmax (hr) | Cav (mg/L) |
|---|---|---|---|---|---|---|---|---|
| 0 | 8 | meropenem 1g q8h IV (SS) | 200 | NC | 7.75 [58.6] | 1.09 [235] | 1.00 [0.500, 3.00] | NC |
The ratio of ELF AUC to plasma AUC at steady state should track the
model’s f_elf partition factor multiplied by the volume
relationship between vc and vp; for typical adults the average
ELF/plasma AUC ratio falls in the 0.2-0.4 range, consistent with
published meropenem ELF penetration estimates of 0.2-0.5 in critically
ill adults (e.g. Frippiat 2015; Lodise 2011).
Comparison against published NCA
The Themans 2019 publication PDF was not located on disk under the
literature tree, so a side-by-side comparison against the article’s
reported Cmax / AUC tables (if any) was not performed. The validation
above relies on (a) self-consistency between the model translation and
the bundle’s Simulated_dataset.csv ELF observations and (b)
the qualitative biological plausibility of the simulated
trajectories.
Assumptions and deviations
-
Article PDF not on disk. The publication (Drugs in R&D,
doi:10.1007/s40268-019-0268-x) was not accessible during extraction.
Demographics, dosing detail beyond the bundle’s
Simulated_dataset.csv, and any published NCA tables could not be cross-checked. The model’s structural form and parameter values come exclusively fromOutput_real_merop_PK_run3.lst’s FINAL PARAMETER ESTIMATE block (postMINIMIZATION SUCCESSFUL). -
Journal mismatch with
Model_Accomodations.text. The bundle’sModel_Accomodations.textdescribes a British Journal of Pharmacology submission (“submitted - July 2019, scenario = 4”); the task metadata names a Drugs in R&D 2019 publication. These are treated as the same body of work at different stages of journal review. -
OMEGA BLOCK(4)reduced to four independent etas. The .mod declares$OMEGA BLOCK(4)but every off-diagonal is held at 0 in both the .mod and the .lst’s FINAL OMEGA matrix, so the nlmixr2 translation uses four independent etas (etalcl,etalvc,etalvp,etalq2).Q2andV3have no associated eta in the source, matching the .mod’s$PKblock. -
NONMEM mixed-unit ELF scaling reconciled to mg-consistent
units. The source
.modparameterises plasma scaling asS1 = V1/1000(which absorbs the g -> mg conversion since AMT is in g and DV is in mg/L) and ELF scaling asS2 = V2/THETA(10)withTHETA(10) = 249. Under that mixed-unit convention NONMEM’s PRED for compartment 2 numerically equalsA2[g] * 249 / V2[L]and the author treats this number as mg/L, which is consistent with a dimensionless meropenem ELF/V2 penetration factor ofTHETA(10) / 1000 = 0.249. This is the partition factorf_elfdeclared in the model file, and the model usesCelf = (peripheral1 / vp) * f_elfto compute ELF concentration in mg/L from a dose supplied in mg. A scatter plot oftypical_celfvs the bundle’sSimulated_dataset.csvELF DV values confirmed the order-of-magnitude consistency of this reconciliation; without that check the natural literal translationCelf = peripheral1 / (vp / 249)would have over-predicted ELF by a factor of 1000. -
Covariate
GFRmapped to canonicalCRCL(raw, not BSA-normalized). The canonical register entry forCRCLis BSA-normalized (mL/min/1.73 m^2); the Themans 2019 model uses raw measured GFR in mL/min (per the .mod $INPUT comment; GFR [mL/min]), and the GFR exponent (0.722) was estimated under that raw-mL/min parameterization. The canonical name is reused with a deviation note (matching the precedent set by theLi_2006_meropenem.Rextraction). -
Dose units converted from g (NONMEM) to mg
(nlmixr2lib). The source dataset uses
AMT [g]andRATE [g/h]; the nlmixr2 model expects mg dosing throughout (per theunits$dosing = "mg"metadata). Users supplying events torxSolveshould use mg amounts (1000 = 1 g) and mg/h rates (2000 = 2 g/h). - Covariates not in the bundle’s data dictionary were not modelled. The .mod $INPUT line referenced `AGE` and `GFRC` columns that the bundle's `Simulated_dataset.csv` does not contain (the bundle's data is reduced to ID, WT, GFR_valAbs, DV, TIME, MDV, CMT, AMT, RATE, SS, II, EVID); the .mod's `$PK` block does not use AGE or GFRC in the covariate equations of run3, so neither is carried into the nlmixr2 model.