Liposomal amphotericin B (Hong 2006)
Source:vignettes/articles/Hong_2006_amphotericinB_liposomal.Rmd
Hong_2006_amphotericinB_liposomal.RmdModel and source
- Citation: Hong Y, Shaw PJ, Nath CE, Yadav SP, Stephen KR, Earl JW, McLachlan AJ. Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother. 2006 Mar;50(3):935-942. doi:10.1128/AAC.50.3.935-942.2006
- Description: Two-compartment population PK model for liposomal amphotericin B (AmBisome) in 39 pediatric oncology patients receiving 1-h IV infusions (Hong 2006). Clearance and central volume scale exponentially with body weight centered at the cohort-median 21 kg; the paper additionally reports substantial between-occasion variability on CL and V1 that is encoded here as IIV on fixed-at-1 multiplicative anchors (Bellanti 2015 IOV-as-IIV pattern).
- Article: Antimicrob Agents Chemother 2006;50(3):935-942 (open access)
Population
The model was developed from a prospective, single-centre, open-label observational pharmacokinetic study of 39 paediatric oncology patients at the Children’s Hospital at Westmead (Sydney, NSW, Australia) (Hong 2006 Table 1). Patients were all neutropenic and febrile, with a mix of diagnoses (15 acute lymphoblastic leukaemia, 4 acute myeloid leukaemia, 20 other), and 16 of the 39 had received a bone marrow transplant (12 allogeneic, 4 autologous). Liposomal amphotericin B (AmBisome) was administered once daily as a 1-h intravenous infusion through a central venous catheter at doses ranging from 0.8 to 5.9 mg/kg/day. A total of 637 plasma concentration observations were collected over 48 dosing courses (mean 13.3 samples per course, range 3-30). Baseline demographics (Hong 2006 Table 1, mean (SD), median, range): age 7.1 years (5.1), 6.5, 0.17-17; weight 28.8 kg (19.8), 21.1, 6.1-84.1; height 119.2 cm (33.7), 118.5, 61.5-190.0; body surface area 0.96 m^2 (0.46), 0.82, 0.32-2.11; serum creatinine 74 umol/L (108), 47, 19-659; gamma glutamyl transferase 105 U/L (211), 39, 11-1398. The cohort was 67% male. The model was fit in NONMEM 5.1.1 with first-order conditional estimation, with lognormal IIV on CL, V1, Q, and V2, additional between-occasion variability (BOV) on CL and V1, and a combined additive plus proportional residual-error model. Robustness and accuracy were verified by a bootstrap of 1000 successful replicates in Wings for NONMEM.
The same information is available programmatically via
readModelDb("Hong_2006_amphotericinB_liposomal")$population.
Source trace
Every numeric value in ini() carries an in-file comment
pointing to the Hong 2006 source location. The table below collects them
in one place for review.
| Equation / parameter | Value | Source location |
|---|---|---|
lcl (CL) |
0.44 L/h | Table 3 row “CL (l h-1)” (RSE 27%); Table 4 row “theta CL” |
lvc (V1) |
3.12 L | Table 3 row “V1 (l)” (RSE 40%); Table 4 row “theta V1” |
lq (Q) |
0.73 L/h | Table 3 row “Q (l h-1)” (RSE 18%); Table 4 row “theta Q” |
lvp (V2) |
18.0 L | Table 3 row “V2 (l)” (RSE 40%); Table 4 row “theta V2” |
e_wt_cl (theta_5) |
0.0152 /kg | Table 3 row “theta_5”; Table 4 row “theta CL ~ WT” (RSE 12%) |
e_wt_vc (theta_6) |
0.0241 /kg | Table 3 row “theta_6”; Table 4 row “theta V1 ~ WT” (RSE 29%) |
etalcl (omega^2 CL = 0.0108) |
0.0108 | Table 3 CL IIV 10%; Table 4 omega^2 CL |
etalvc (omega^2 V1 = 0.0450) |
0.0450 | Table 4 bootstrap omega^2 V1 (original failed; see notes below) |
etalq (omega^2 Q = 0.593) |
0.593 | Table 3 Q IIV 77%; Table 4 omega^2 Q |
etalvp (omega^2 V2 = 0.546) |
0.546 | Table 3 V2 IIV 74%; Table 4 omega^2 V2 |
etalcl_bov_mult (pi^2 = 0.209) |
0.209 | Table 3 CL BOV 46%; Table 4 pi^2 CL |
etalvc_bov_mult (pi^2 = 0.319) |
0.319 | Table 3 V1 BOV 56%; Table 4 pi^2 V1 |
propSd (27% proportional) |
0.27 | Table 3 row “Proportional (%)” (RSE 7%); Table 4 sigma^2 prop |
addSd (0.034 mg/L additive) |
0.034 | Table 3 row “Additive (mg l-1)” (RSE 24%); Table 4 sigma^2 add |
| WT centering (21 kg) | 21 | Methods text after Table 2 footnote: WTmedian = 21 kg |
| 2-cmt IV zero-order infusion | n/a | Abstract; Results “Population pharmacokinetic modeling” para 1 |
| Combined add + prop residual | n/a | Methods Eq. (combined error model); Results para 2 |
| Lognormal IIV on CL/V1/Q/V2 | n/a | Methods “Development of base population pharmacokinetic model” |
| BOV on CL and V1 (BLOCK(2) SAME) | n/a | Methods Eq. (BOV definition); Results para 2 |
IIV / BOV variance derivation. Hong 2006 reports IIV in Table 3 as a
percentage; the corresponding numbers in Table 4 are
omega^2 (the variance on the log scale). The “%” values in
Table 3 therefore represent the log-scale SD (omega)
expressed as a percent, so omega^2 ~ ("%"/100)^2:
- CL: 10% IIV ->
omega^2 = 0.0108(Table 4) - V1: failed-to-estimate in Table 3; bootstrap
omega^2 = 0.0450(Table 4) - Q: 77% IIV ->
omega^2 = 0.593(Table 4) - V2: 74% IIV ->
omega^2 = 0.546(Table 4) - CL BOV: 46% ->
pi^2 = 0.209(Table 4) - V1 BOV: 56% ->
pi^2 = 0.319(Table 4)
Virtual cohort
Original observed data are not publicly available. The cohort below covers four scenarios bracketing the paper’s body-weight range: a typical patient at the cohort median weight (WT = 21 kg), a small infant (WT = 10 kg), a school-aged child (WT = 35 kg), and an adolescent (WT = 60 kg). All scenarios receive a 1-h IV infusion of liposomal amphotericin B once daily for 7 doses at 3 mg/kg/day (the mid-range prophylactic regimen described in Hong 2006 Methods and Results).
set.seed(20260531)
n_sub <- 200L
build_arm <- function(label, wt_kg, dose_mg_per_kg_per_day, id_offset) {
ids <- id_offset + seq_len(n_sub)
dose_amt_mg <- wt_kg * dose_mg_per_kg_per_day
infusion_h <- 1
dose_times <- seq(0, 144, by = 24) # seven doses, once daily
dose_rows <- tidyr::expand_grid(id = ids, time = dose_times) |>
mutate(
evid = 1L,
amt = dose_amt_mg,
cmt = "central",
rate = dose_amt_mg / infusion_h, # 1-h IV infusion
cohort = label,
WT = wt_kg,
dose_mgkg = dose_mg_per_kg_per_day
)
obs_times <- c(seq(0, 24, by = 0.25),
seq(25, 168, by = 2),
seq(170, 240, by = 4))
obs_rows <- tidyr::expand_grid(id = ids, time = obs_times) |>
mutate(
evid = 0L,
amt = 0,
cmt = NA_character_,
rate = 0,
cohort = label,
WT = wt_kg,
dose_mgkg = dose_mg_per_kg_per_day
)
bind_rows(dose_rows, obs_rows) |> arrange(id, time, desc(evid))
}
events <- bind_rows(
build_arm("infant_10kg", 10, 3, 0L),
build_arm("typical_21kg", 21, 3, 200L),
build_arm("schoolage_35kg", 35, 3, 400L),
build_arm("adolescent_60kg", 60, 3, 600L)
)
stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid")])))Simulation
mod <- readModelDb("Hong_2006_amphotericinB_liposomal")
sim <- rxode2::rxSolve(
mod,
events = events,
keep = c("cohort", "WT", "dose_mgkg")
) |> as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'For typical-value comparisons against the Hong 2006 Table 3 point estimates, also simulate with the random effects zeroed:
mod_typical <- mod |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_typical <- rxode2::rxSolve(
mod_typical,
events = events,
keep = c("cohort", "WT", "dose_mgkg")
) |> as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalq', 'etalvp', 'etalcl_bov_mult', 'etalvc_bov_mult'
#> Warning: multi-subject simulation without without 'omega'Concentration-time profile (typical-value, 1.8 mg/kg)
Hong 2006 Figure 2 shows the representative concentration-time profile of a patient treated with 1-h IV infusions of L-AmB at 1.8 mg/kg per day over a single 24-h dosing interval. To reproduce that figure, we simulate a typical 21-kg patient (cohort median) at the 1.8 mg/kg regimen, then plot the first 24 hours after dose 1.
events_fig2 <- build_arm("fig2_1.8mgkg", 21, 1.8, 0L)
sim_fig2 <- rxode2::rxSolve(mod_typical, events = events_fig2,
keep = c("cohort", "WT", "dose_mgkg")) |>
as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalq', 'etalvp', 'etalcl_bov_mult', 'etalvc_bov_mult'
#> Warning: multi-subject simulation without without 'omega'
sim_fig2 |>
filter(time <= 24, id == min(id)) |>
ggplot(aes(time, Cc)) +
geom_line(linewidth = 0.9) +
labs(
x = "Time after first dose (h)",
y = "L-AmB plasma concentration (mg/L)",
title = "Replicates Hong 2006 Figure 2: typical-value Cc over one 24-h interval",
subtitle = "1-h IV infusion of L-AmB at 1.8 mg/kg in a typical 21 kg patient"
)
Concentration-time profile by weight cohort
sim |>
group_by(cohort, time) |>
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, Q50, colour = cohort, fill = cohort)) +
geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.2, colour = NA) +
geom_line() +
scale_y_log10() +
labs(
x = "Time (h)",
y = "Simulated L-AmB Cc (mg/L, log scale)",
title = "Simulated L-AmB by weight cohort, 3 mg/kg/day x 7 doses",
caption = "Lines: median; ribbons: 5th-95th percentile across 200 simulated subjects."
)
#> Warning in scale_y_log10(): log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
PKNCA validation (steady-state, last dosing interval)
The block below characterises steady-state Cmax, Cmin (= Ctau),
AUC0-tau, average concentration, and the inferred terminal half-life
from the typical-value time course over the seventh dosing interval
(tau = 24 h). The treatment grouping is
cohort, matching the four weight-stratified scenarios.
last_dose_time <- 144 # seventh dose at t = 144 h; tau = 24 h
sim_nca <- sim_typical |>
filter(!is.na(Cc), time >= last_dose_time, time <= last_dose_time + 24) |>
mutate(time_in_tau = time - last_dose_time) |>
select(id, time = time_in_tau, Cc, cohort)
dose_df <- events |>
filter(evid == 1, time == last_dose_time) |>
select(id, time, amt, cohort) |>
mutate(time = 0)
conc_obj <- PKNCA::PKNCAconc(sim_nca, Cc ~ time | cohort + id,
concu = "mg/L", timeu = "hr")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | cohort + id,
doseu = "mg")
intervals <- data.frame(
start = 0,
end = 24,
cmax = TRUE,
tmax = TRUE,
cmin = TRUE,
auclast = TRUE,
cav = TRUE
)
nca_res <- PKNCA::pk.nca(
PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
)
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (1) is not allowed
nca_summary <- summary(nca_res)
knitr::kable(
nca_summary,
caption = "Simulated steady-state NCA parameters (typical-value, seventh dose interval, tau = 24 h) by weight cohort."
)| Interval Start | Interval End | cohort | N | AUClast (hr*mg/L) | Cmax (mg/L) | Cmin (mg/L) | Tmax (hr) | Cav (mg/L) |
|---|---|---|---|---|---|---|---|---|
| 0 | 24 | adolescent_60kg | 200 | NC | 24.7 [0.000] | 4.45 [0.000] | 1.00 [1.00, 1.00] | NC |
| 0 | 24 | infant_10kg | 200 | NC | 11.7 [0.000] | 1.81 [0.000] | 1.00 [1.00, 1.00] | NC |
| 0 | 24 | schoolage_35kg | 200 | NC | 24.6 [0.000] | 4.04 [0.000] | 1.00 [1.00, 1.00] | NC |
| 0 | 24 | typical_21kg | 200 | NC | 19.8 [0.000] | 3.13 [0.000] | 1.00 [1.00, 1.00] | NC |
Terminal half-life (typical-value)
Hong 2006 reports a secondary terminal half-life
t1/2,beta = 59.4 SD 36.5 h derived from individual Bayesian
posterior estimates. For a typical 2-compartment IV model with
CL = 0.44 L/h, V1 = 3.12 L, Q = 0.73 L/h, V2 = 18.0 L, the
two macro-rate constants alpha and beta
satisfy alpha + beta = kel + k12 + k21 and
alpha * beta = kel * k21, giving
beta ~= 0.0142 1/h and t1/2,beta ~= 48.8 h for
the typical (21 kg) subject. The figure below evaluates the
post-infusion log-linear decline numerically from the stopped-dose
simulation.
event_singledose <- build_arm("typical_21kg_single", 21, 3, 0L) |>
filter(time <= 200, !(evid == 1 & time > 0)) # one dose only
sim_single <- rxode2::rxSolve(mod_typical, events = event_singledose,
keep = c("WT")) |>
as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalq', 'etalvp', 'etalcl_bov_mult', 'etalvc_bov_mult'
#> Warning: multi-subject simulation without without 'omega'
# Estimate terminal slope on natural log scale from the 72-200 h window
tail_fit <- sim_single |>
filter(id == min(id), time >= 72, time <= 200, Cc > 0) |>
mutate(lnCc = log(Cc))
fit <- lm(lnCc ~ time, data = tail_fit)
lambda_z <- -coef(fit)[["time"]]
tbeta_h <- log(2) / lambda_z
knitr::kable(
tibble(
quantity = c(
"Simulated terminal slope lambda_z (1/h)",
"Simulated terminal half-life t1/2,beta (h)",
"Published t1/2,beta (mean SD 1/h)",
"Analytical beta from typical THETAs (1/h)",
"Analytical t1/2,beta from typical THETAs (h)"
),
value = c(
sprintf("%.4f", lambda_z),
sprintf("%.1f", tbeta_h),
"59.4 +/- 36.5",
"0.0142",
"48.8"
)
),
caption = "Simulated vs published terminal half-life for the typical 21 kg subject."
)| quantity | value |
|---|---|
| Simulated terminal slope lambda_z (1/h) | 0.0143 |
| Simulated terminal half-life t1/2,beta (h) | 48.6 |
| Published t1/2,beta (mean SD 1/h) | 59.4 +/- 36.5 |
| Analytical beta from typical THETAs (1/h) | 0.0142 |
| Analytical t1/2,beta from typical THETAs (h) | 48.8 |
Steady-state volume of distribution (typical-value)
Hong 2006 reports a secondary Vss = 1.14 +/- 0.68 L/kg
from individual Bayesian estimates. For the typical 21 kg subject the
model gives
Vss = (V1 + V2) / WT = (3.12 + 18.0) / 21 = 1.006 L/kg,
comparable to the published mean.
vc_typ <- 3.12
vp_typ <- 18.0
wt_typ <- 21
vss_lkg <- (vc_typ + vp_typ) / wt_typ
knitr::kable(
tibble(
quantity = c(
"Simulated Vss for typical 21 kg subject (L/kg)",
"Published Vss (mean SD 1/kg)"
),
value = c(
sprintf("%.3f", vss_lkg),
"1.14 +/- 0.68"
)
),
caption = "Simulated vs published Vss for the typical 21 kg subject."
)| quantity | value |
|---|---|
| Simulated Vss for typical 21 kg subject (L/kg) | 1.006 |
| Published Vss (mean SD 1/kg) | 1.14 +/- 0.68 |
Cmax,ss / MIC target attainment
Hong 2006 demonstrated that Cmax,ss / MIC discriminates
between complete and partial clinical responses to L-AmB in patients
with proven invasive fungal infection (Hong 2006 Table 5 and Figure 3).
The authors then used the population PK model to explore whether
weight-stratified dosing achieves the proposed target of
Cmax,ss / MIC > 50 for canonical MICs of 0.5 mg/L
(Candida) and 1.0 mg/L (Aspergillus). The table below reproduces that
calculation using the typical-value Cmax,ss at the seventh
dose interval for the four weight cohorts at 3 mg/kg/day.
cmax_ss <- sim_typical |>
filter(time >= last_dose_time, time <= last_dose_time + 24) |>
group_by(cohort, WT, dose_mgkg) |>
summarise(Cmax_ss_mgL = max(Cc, na.rm = TRUE), .groups = "drop") |>
mutate(
Cmaxss_over_MIC_Candida = round(Cmax_ss_mgL / 0.5, 1),
Cmaxss_over_MIC_Aspergillus = round(Cmax_ss_mgL / 1.0, 1)
)
knitr::kable(
cmax_ss,
digits = 2,
caption = "Typical-value Cmax,ss and Cmax,ss/MIC ratios by weight cohort at 3 mg/kg/day, day 7. Hong 2006 proposed Cmax,ss/MIC >= 50 as the antifungal efficacy target."
)| cohort | WT | dose_mgkg | Cmax_ss_mgL | Cmaxss_over_MIC_Candida | Cmaxss_over_MIC_Aspergillus |
|---|---|---|---|---|---|
| adolescent_60kg | 60 | 3 | 24.66 | 49.3 | 24.7 |
| infant_10kg | 10 | 3 | 11.75 | 23.5 | 11.7 |
| schoolage_35kg | 35 | 3 | 24.62 | 49.2 | 24.6 |
| typical_21kg | 21 | 3 | 19.78 | 39.6 | 19.8 |
Assumptions and deviations
-
Between-occasion variability (BOV) encoded as IIV on multiplicative anchors. Hong 2006 estimates BOV on CL (46%) and V1 (56%) via NONMEM’s
$OMEGA BLOCK(2) SAME(a single magnitude shared across all dosing occasions for a given subject). nlmixr2lib has no canonical pattern for occasion-keyed IOV without anOCCcovariate column, so the BOV variance is carried here as ordinary IIV on fixed-at-1 multiplicative anchorslcl_bov_multandlvc_bov_mult(following the Bellanti 2015 deferoxamine precedent). The total log-scale variance for the typical subject is thereforeetalcl + etalcl_bov_mult = 0.0108 + 0.209 = 0.220(CL) and `etalvc + etalvc_bov_mult = 0.045- 0.319 = 0.364` (V1). The model preserves the population-level spread but loses the within-subject between-occasion drift that the paper estimates (a single simulated subject does not switch parameter values between courses).
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IIV on V1 from the bootstrap. Hong 2006 Table 3 leaves the IIV V1 column blank because the original NONMEM fit did not estimate a stable
omega^2for V1 (the Discussion notes that BOV exceeded IIV on V1, and NONMEM had difficulty disentangling them). The bootstrap mean from 1000 successful replicates (omega^2 V1 = 0.0450, Table- is used here as the best available point estimate. Treat this number as a lower bound on the V1 IIV; the paper does not commit to a published value.
Weight is time-varying across dosing courses. Hong 2006 Methods states that covariate values were updated per course; the model encodes WT as time-varying. For the simulations above we hold WT fixed within each cohort (matched to the median weight for that band). Users simulating real per-patient time-varying WT should supply the column at every record.
No erratum identified. A Crossref search for “Hong 2006 liposomal amphotericin erratum / corrigendum” returned no relevant results in 2026-05-31; the model uses the values as published in the original paper without correction.
Race / ethnicity not reported. Hong 2006 does not report race / ethnicity for the cohort (the study was conducted at a single centre in Sydney). No race-based stratification or covariate is included.
Renal-function markers not retained. The paper screened serum creatinine and other renal markers as covariates but did not retain them because renal elimination is a minor pathway for L-AmB (Hong 2006 Discussion). The model has no renal-function covariate.
Sex not retained. Sex did not significantly affect L-AmB PK in the Mann-Whitney U test (Hong 2006 Results). The model has no sex covariate.