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Finafloxacin (Taubert 2018)

Source: vignettes/articles/Taubert_2018_finafloxacin.Rmd
Taubert_2018_finafloxacin.Rmd

Model and source

  • Citation: Taubert M, Luckermann M, Vente A, Dalhoff A, Fuhr U. Population pharmacokinetics of finafloxacin in healthy volunteers and patients with complicated urinary tract infections. Antimicrob Agents Chemother. 2018;62(4):e02328-17. doi:10.1128/AAC.02328-17
  • Description: Two-compartment population PK model for finafloxacin (a novel fluoroquinolone with enhanced antibacterial activity at acidic pH) with linear elimination, parallel first-order plus zero-order oral absorption (each with its own absorption lag time), an additive renal + non-renal clearance decomposition, and a cumulative-urinary excretion compartment. Built from pooled data of 266 subjects across three trials: 127 healthy volunteers (Trial I oral 25-1,000 mg/day; Trial II IV 200-1,000 mg/day) and 139 patients with complicated urinary tract infections (Trial III IV 800 mg/day, 60-min infusions). Covariates: body surface area on the central volume of distribution (power form, exponent 1.50, reference 1.829 m^2) and healthy / patient cohort status (DIS_HEALTHY) on both the renal and non-renal clearance arms. The paper-reported total apparent clearance (20.9 L/h healthy; -29% in patients) and population-specific fraction renally excreted (FER1 = 0.40 healthy, FER2 = 0.21 patient) are re-parameterised into the canonical lcl_renal + lcl_nonren additive decomposition; the typical values are anchored to DIS_HEALTHY = 0 (patient reference) per the inst/references/covariate-columns.md DIS_HEALTHY convention. The IIV translation between the paper and the re-parameterised forms is documented in the validation vignette Assumptions and deviations (Taubert 2018).
  • Article: https://doi.org/10.1128/AAC.02328-17

Population

Taubert 2018 fit a unified population PK model to pooled data from 266 subjects across three trials (paper Table 1):

  • Trial I (n = 77): healthy adult volunteers receiving oral finafloxacin 25-1,000 mg/day (single and multiple ascending doses); median weight 75.3 kg (61-97.7), median height 176.7 cm (161-190), median age 42.5 years (19-55), 71 male.
  • Trial II (n = 50): healthy adult volunteers receiving IV finafloxacin 200-1,000 mg/day; median weight 76.5 kg (50.9-112.4), median height 174.5 cm (138-200), median age 41.5 years (19-63), 42 male.
  • Trial III (n = 139): hospitalised patients with complicated urinary tract infections or acute complicated / uncomplicated pyelonephritis receiving IV finafloxacin 800 mg/day for 5 or 10 days (60-min short infusions); median weight 73.5 kg (64-140), median height 164 cm (145-186), median age 61 years (19-90), 21 male.

A total of 3,235 plasma samples and 633 urine samples were modelled (ClinicalTrials.gov NCT01928433). The same information is available programmatically via readModelDb("Taubert_2018_finafloxacin")$population.

Source trace

The per-parameter origin is recorded as an in-file comment next to each ini() entry in inst/modeldb/specificDrugs/Taubert_2018_finafloxacin.R. The table below collects them in one place for review.

Equation / parameter Value Source location
lcl_renal log(3.12) (= log(20.9 * 0.71 * 0.21)) Table 3 (CL_total, patient effect, FER2)
lcl_nonren log(11.72) (= log(20.9 * 0.71 * 0.79)) Table 3 (CL_total, patient effect, 1 - FER2)
lvc log(46.9) Table 3 (Vc)
lq log(2.80) Table 3 (Q)
lvp log(43.1) Table 3 (Vp)
e_bsa_vc 1.50 Table 3 (BSA on Vc)
e_dis_healthy_cl_renal log(8.36 / 3.12) = 0.985 Table 3 (FER1 / FER2, with patient CL effect)
e_dis_healthy_cl_nonren log(12.54 / 11.72) = 0.068 Table 3 ((1 - FER1) / (1 - FER2), with patient CL effect)
lfdepot log(0.75) Table 3 oral (F)
logitf1st logit(0.77) Table 3 oral (f1st)
lka log(6.61) Table 3 oral (Ka)
ltlag1 log(0.22) Table 3 oral (LAG1)
ld0 log(7.77) Table 3 oral (D0)
ltlag2 log(0.54) Table 3 oral (LAG2)
etalcl_renal log(1 + 0.57^2) combined CL_total IIV (54%) + FER1 IIV (19%)
etalcl_nonren log(1 + 0.54^2) Table 3 (IIV on CL_total)
etalvc, etalq, etalvp log(1 + CV^2) Table 3 (IIV %CV per parameter)
oral absorption IIVs log(1 + CV^2) Table 3 oral (IIV %CV per parameter)
addSd, propSd 0.001, 0.24 Table 3 (IV plasma RUV)
addSd_urineAmt, propSd_urineAmt 0.001, 0.33 Table 3 (IV urine RUV)
Two-compartment ODE structure n/a Methods, Population pharmacokinetic analysis
Parallel first-order + zero-order absorption n/a Results, Oral absorption model
Urinary excretion compartment n/a Methods (output compartment for renal arm)

Virtual cohort

The original observed data are not publicly available. The simulations below use two virtual cohorts whose covariate distributions approximate the Trial II (healthy IV) and Trial III (patient IV) demographics from Table 1.

set.seed(20180101)

make_cohort <- function(n, wt_mu, wt_sd, ht_mu, ht_sd, pct_female, dis_healthy, id_offset = 0L) {
  tibble(
    id          = id_offset + seq_len(n),
    WT          = pmax(40, rnorm(n, mean = wt_mu, sd = wt_sd)),
    HT          = pmax(140, rnorm(n, mean = ht_mu, sd = ht_sd)),
    SEXF        = rbinom(n, size = 1, prob = pct_female / 100),
    DIS_HEALTHY = dis_healthy
  ) |>
    mutate(BSA = sqrt(WT * HT / 3600))
}

n_per_cohort <- 200L

cohort_healthy <- make_cohort(
  n          = n_per_cohort,
  wt_mu      = 76.5,
  wt_sd      = 12.0,
  ht_mu      = 174.5,
  ht_sd      = 9.0,
  pct_female = 16.0,
  dis_healthy = 1L,
  id_offset  = 0L
) |>
  mutate(cohort = "Healthy (Trial II)")

cohort_patient <- make_cohort(
  n          = n_per_cohort,
  wt_mu      = 73.5,
  wt_sd      = 15.0,
  ht_mu      = 164.0,
  ht_sd      = 9.0,
  pct_female = 85.0,
  dis_healthy = 0L,
  id_offset  = n_per_cohort
) |>
  mutate(cohort = "Patient (Trial III)")

cohorts <- bind_rows(cohort_healthy, cohort_patient)

Each subject receives 800 mg IV finafloxacin once daily as a 60-min infusion (rate = amt / duration = 800 mg/h) for seven days; observations are sampled densely across the final dosing interval to characterise steady-state PK.

dose_times <- seq(0, 24 * 6, by = 24)
obs_times  <- c(
  seq(24 * 6, 24 * 6 + 1, by = 0.05),
  seq(24 * 6 + 1.1, 24 * 6 + 23.9, by = 0.5),
  24 * 7
)

dose_rows <- cohorts |>
  tidyr::crossing(time = dose_times) |>
  mutate(
    evid = 1,
    amt  = 800,
    cmt  = "central",
    rate = 800,
    dv   = NA_real_
  )

obs_rows <- cohorts |>
  tidyr::crossing(time = obs_times) |>
  mutate(
    evid = 0,
    amt  = NA_real_,
    cmt  = "Cc",
    rate = 0,
    dv   = NA_real_
  )

events <- bind_rows(dose_rows, obs_rows) |>
  arrange(id, time, desc(evid))

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

Simulation 

mod <- readModelDb("Taubert_2018_finafloxacin")

sim <- rxode2::rxSolve(
  mod,
  events = events,
  keep   = c("cohort", "WT", "HT", "BSA", "DIS_HEALTHY")
) |>
  as.data.frame() |>
  dplyr::filter(time >= 24 * 6)
#> ℹ parameter labels from comments will be replaced by 'label()'

Replicate published figures 

# Replicates the steady-state concentration-time pattern visible in Figure 1
# (b, c) and Figure 3 of Taubert 2018: median + 90% prediction interval at
# steady state for healthy volunteers (Trial II) vs. cUTI patients (Trial III).
sim |>
  mutate(time_h = time - 24 * 6) |>
  group_by(cohort, time_h) |>
  summarise(
    Q05 = quantile(Cc, 0.05, na.rm = TRUE),
    Q50 = quantile(Cc, 0.50, na.rm = TRUE),
    Q95 = quantile(Cc, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  ggplot(aes(time_h, Q50, fill = cohort, colour = cohort)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25, colour = NA) +
  geom_line(linewidth = 0.7) +
  scale_y_log10() +
  labs(
    x = "Time after dose (h)",
    y = "Finafloxacin plasma concentration (mg/L)",
    fill   = NULL,
    colour = NULL,
    title  = "Steady-state plasma profile after 800 mg IV q24h",
    caption = "Simulated typical-value + 90% PI at day 7."
  ) +
  theme_minimal()

PKNCA validation

Use PKNCA to compute Cmax, Tmax, AUC, and half-life on the simulated final dosing interval (24*6 < time <= 24*7) so the results align with the steady-state Table 4 of Taubert 2018.

sim_nca <- sim |>
  dplyr::filter(time > 24 * 6) |>
  dplyr::mutate(time_h = time - 24 * 6) |>
  dplyr::filter(!is.na(Cc)) |>
  dplyr::select(id, time = time_h, Cc, cohort, WT)

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

dose_df <- cohorts |>
  dplyr::mutate(time = 0, amt = 800)

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

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

nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_res  <- PKNCA::pk.nca(nca_data)
#> 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
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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
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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
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#> 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
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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
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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
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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

nca_long <- as.data.frame(nca_res$result) |>
  dplyr::filter(PPTESTCD %in% c("cmax", "tmax", "auclast", "half.life"))

nca_summary <- nca_long |>
  dplyr::group_by(cohort, PPTESTCD) |>
  dplyr::summarise(
    median = stats::median(PPORRES, na.rm = TRUE),
    q025   = stats::quantile(PPORRES, 0.025, na.rm = TRUE),
    q975   = stats::quantile(PPORRES, 0.975, na.rm = TRUE),
    .groups = "drop"
  ) |>
  dplyr::mutate(
    formatted = sprintf("%.2f (%.2f-%.2f)", median, q025, q975)
  ) |>
  dplyr::select(cohort, PPTESTCD, formatted) |>
  tidyr::pivot_wider(names_from = PPTESTCD, values_from = formatted)

knitr::kable(
  nca_summary,
  caption = "Simulated steady-state NCA parameters (median, 95% prediction interval) by cohort."
)
Simulated steady-state NCA parameters (median, 95% prediction interval) by cohort.
cohort auclast cmax half.life tmax
Healthy (Trial II) NA (NA-NA) 12.34 (8.63-19.50) 11.59 (3.30-50.27) 1.00 (1.00-1.00)
Patient (Trial III) NA (NA-NA) 14.56 (9.56-20.98) 12.61 (4.12-34.11) 1.00 (1.00-1.00)

Comparison against published NCA (Table 4 of Taubert 2018)

Paper Table 4 reports steady-state plasma PK parameters from a Monte Carlo simulation of 800 mg/day IV finafloxacin in Trial II (healthy) and Trial III (patient) populations. Note that the paper’s tabulated AUC is the steady-state AUC over the 24-h dosing interval (equivalent to AUClast on a 0-24 h window at steady state), and that T1/2(P) is the plasma (early-distribution) phase half-life calculated as ln(2) * Vc / CL.

Parameter Trial II (healthy) Trial III (patient)
AUC (mg*h/L) 38 (15-96) 54 (22-134)
Cmax (mg/L) 14 (9-23) 16 (10-27)
Tmax (h) 1.12 (1.01-1.37) 1.13 (1.01-1.45)
T1/2 P (h) 1.66 (0.67-4.0) 2.15 (0.87-5.27)
T1/2 T (h) 12.5 (6.21-25.2) 13.3 (6.5-27.1)

Differences of more than 20% between the simulated table and the paper Table 4 typically indicate a transcription error in the source-trace; investigate them in the model file rather than tuning parameters.

Assumptions and deviations

  • CL_total + FER re-parameterised to lcl_renal + lcl_nonren. Taubert 2018 reports total apparent clearance (20.9 L/h, with a -29% patient effect) and two population-specific fractions renally excreted (FER1 = 0.40 healthy, FER2 = 0.21 patient). The model file re-parameterises this into the canonical lcl_renal + lcl_nonren additive decomposition registered in parameter-names.md. Typical CL values at both DIS_HEALTHY levels reproduce the paper exactly; the IIV translation is approximated using log-additivity (var(log cl_renal) ~ var(log CL_total) + var(log FER) under independence of the paper’s CL_total and FER etas). The healthy-derived combined IIV (~57% CV) is used as the canonical etalcl_renal; the paper’s higher patient-population FER2 IIV (62%) reflects a poor urine fit in cUTI patients (R^2 = 0.34) that the paper itself flags as not reliable.
  • IOV ignored. Paper Table 3 reports inter-occasion variability (IOV) separately from inter-individual variability. The model file uses a single random-effect set per parameter, so the IOV term is absorbed into the IIV. Users running occasion-specific simulations should add etaiov_<param> terms (out of scope for the unified library model).
  • BSA formula unspecified by paper. Table 3 footnote a anchors the BSA reference at a 70 kg / 172 cm subject without naming a formula. The model uses Mosteller (sqrt(W * H / 3600)), which gives 1.829 m^2 at the reference and differs from DuBois (1.827 m^2) and Haycock (1.836 m^2) by less than 0.5% at the reference point. The choice is numerically inconsequential.
  • Residual-error values are SDs. Table 3 reports residuals as bare decimal values (0.24 plasma proportional, 0.33 urine proportional, 0.001 additive). These are interpreted as SDs (i.e., 24% / 33% / 0.001 mg L^-1) based on the tight bootstrap 95% CIs around 0.24 ([0.22, 0.26]) and the popPK-reporting convention. The supplementary NONMEM control stream is not on disk to confirm the variance-vs-SD interpretation directly.
  • Oral residual errors not encoded. Table 3 reports separate residuals for the sequential oral fit (additive 0.03 mg L^-1, proportional 0.14). The model file uses only the IV-data plasma residuals as the unified default. Users running an oral-only simulation may switch addSd to 0.03 and propSd to 0.14 to match the oral-data residuals.
  • No oral simulation here. The validation comparison against Table 4 uses IV 800 mg/day at steady state (the paper’s published comparison case). Oral dosing is supported by the model via two dose records per oral dose (cmt = "depot" for the first-order arm, cmt = "depot2" with rate = -2 for the zero-order arm); see the model file’s model() block comments for the event-table recipe.
  • Sex distribution approximate. Trial-specific sex distributions in the virtual cohort use Bernoulli(p) draws from the male-female ratios in paper Table 1 (Trial II: 16% female; Trial III: 85% female), but SEXF is not used as a covariate in the final model – it is included only to document the cohort composition.
  • Race / ethnicity not reported in the paper. The population metadata notes the omission.
  • Cumulative urine output simulated but not compared against the paper. The model carries a urine compartment with urineAmt as the derived observation; the paper’s urine fit in patients was poor (R^2 = 0.34) and the paper does not provide a per-interval urine NCA table to compare against.