library(nlmixr2lib)
library(rxode2)
#> rxode2 5.0.2 using 2 threads (see ?getRxThreads)
#> no cache: create with `rxCreateCache()`
library(dplyr)
#>
#> Attaching package: 'dplyr'
#> The following objects are masked from 'package:stats':
#>
#> filter, lag
#> The following objects are masked from 'package:base':
#>
#> intersect, setdiff, setequal, union
library(tidyr)
library(ggplot2)
library(PKNCA)
#>
#> Attaching package: 'PKNCA'
#> The following object is masked from 'package:stats':
#>
#> filterPertuzumab (PERJETA) population PK in solid tumors
Simulate pertuzumab concentration-time profiles using the final population PK model of Garg et al. (2014) in patients with HER2-targeted solid tumors. The source analysis pooled 4,525 pertuzumab serum concentrations from 481 patients across five phase I/Ib studies, six phase II studies, and the pivotal phase III CLEOPATRA trial.
The final model is a two-compartment linear PK model with first-order elimination from the central compartment:
with , , , and . Concentrations carried inside the ODEs are in mg/L (= ug/mL) because dose is mg and volumes are L.
Pertuzumab in the 2-25 mg/kg dose range exhibits dose-proportional (linear) PK; nonlinear (target-mediated) PK was suggested only at the lowest 0.5 mg/kg single dose in three phase Ia patients, and those data were excluded from the final analysis. Reported terminal elimination half-life is 18 days, supporting every-3-week dosing.
- Article: https://doi.org/10.1007/s00280-014-2560-3
- PubMed (PMID 25119184): https://pubmed.ncbi.nlm.nih.gov/25119184/
Source trace
The per-parameter origin is recorded as an in-file comment next to
each ini() entry in
inst/modeldb/specificDrugs/Garg_2014_pertuzumab.R. The
table below collects the mapping in one place for reviewer audit.
| Element | Source location | Value / form |
|---|---|---|
| Two-compartment linear PK; IV into central | Garg 2014 Results “Pertuzumab PK” (page 822) | d/dt(central) = -kel*central - k12*central + k21*peripheral1 |
| Typical linear CL | Garg 2014 Table 1, theta1 | 0.235 L/day |
| Typical Vc | Garg 2014 Table 1, theta2 | 3.11 L |
| Typical Q | Garg 2014 Table 1, theta3 | 0.534 L/day |
| Typical Vp | Garg 2014 Table 1, theta4 | 2.46 L |
| Reference subject | Garg 2014 Table 1 footnote and CL/Vc/Vp covariate equations (page 823) | LBW = 48 kg, ALBU = 3.9 g/dL |
| LBW on CL (theta5) | Garg 2014 Table 1 and CL covariate equation | Power: (LBW/48)^0.516
|
| LBW on Vc (theta6) | Garg 2014 Table 1 and Vc covariate equation | Power: (LBW/48)^0.747
|
| ALB (ALBU) on CL (theta7) | Garg 2014 Table 1 and CL covariate equation | Power: (ALBU/3.9)^-1.06
|
| LBW on Vp (theta8) | Garg 2014 Table 1 and Vp covariate equation | Power: (LBW/48)^0.83
|
| IIV on CL (34.1% CV), Vc (18.5% CV), Vp (45.9% CV) | Garg 2014 Table 1 (BSV column) | 3x3 block via omega^2 = log(CV^2 + 1) -> 0.1100,
0.0337, 0.1912 |
| Off-diagonal IIV covariances | Garg 2014 Table 1 footnote (“Covariance of PK parameters: omega_CL,Vc = 0.0239, omega_CL,Vp = -0.0416, omega_Vc,Vp = 0.000179”) | Lower-triangle: 0.0239, -0.0416, 0.000179 |
| Proportional residual error (18.1%) | Garg 2014 Table 1 (“Proportional residual error (%)”); paper Methods “additive residual on log-transformed concentration” -> proportional in nlmixr2 linear space | propSd = 0.181 |
Covariate column naming
| Source column | Canonical column used here | Notes |
|---|---|---|
LBW |
LBM (kg) |
Lean body weight; same biological quantity as canonical lean body mass. Reference 48 kg (cohort median). |
ALBU |
ALB (g/dL) |
Baseline serum albumin in US conventional units. Reference 3.9 g/dL. |
Population
The model was estimated from 481 patients and 4,525 pertuzumab serum concentrations pooled across 12 studies (five phase I/Ib, six phase II, one phase III: CLEOPATRA). 392 patients (81.5%) received pertuzumab without chemotherapy; the remainder received pertuzumab with chemotherapy (gemcitabine, capecitabine, or docetaxel) and/or other targeted therapy (trastuzumab or erlotinib). Median age was 60 years, median body weight 72 kg, 62% female, and 95.4% non-Japanese. Almost all patients (479/481, 99.6%) had ECOG performance status 0 or 1. Patients received body-weight- based dosing (0.5-25 mg/kg q3w) or one of two fixed-dose regimens (1050 mg q3w, n = 96; 840 mg loading + 420 mg q3w maintenance, n = 346 - the labelled regimen). Phase Ia patients receiving 0.5 mg/kg (n = 3) were excluded after preliminary nonlinear PK exploration was inconclusive at the lowest dose.
The same information is available programmatically:
readModelDb("Garg_2014_pertuzumab")$meta$populationVirtual cohort
The source paper does not publish per-subject baseline covariates (Online Resource 2 gives aggregate summaries only). The cohort below is a pragmatic approximation for simulation, centred so reference-subject predictions reproduce the Table 1 typical values (reference: LBW 48 kg, ALB 3.9 g/dL).
set.seed(2014)
# Virtual cohort per-arm constructor. id_offset keeps subject IDs disjoint
# across the two regimen arms so rxSolve does not collapse duplicate IDs
# into single (wrong) subjects.
make_cohort <- function(n, regimen, id_offset = 0L) {
tibble::tibble(
id = id_offset + seq_len(n),
regimen = regimen,
LBM = pmin(pmax(rnorm(n, 48, 9), 30), 80), # kg; centred at 48 kg (reference)
ALB = pmin(pmax(rnorm(n, 3.9, 0.45), 2.5), 5.2) # g/dL; centred at 3.9 g/dL (reference)
)
}
cohort <- dplyr::bind_rows(
make_cohort(250, "840/420 mg q3w", id_offset = 0L),
make_cohort(250, "1050 mg q3w", id_offset = 250L)
)
# Sanity: IDs are disjoint across cohorts
stopifnot(!anyDuplicated(cohort$id))Dosing regimens
The two labelled fixed-dose regimens evaluated by Garg 2014 Figure 2 are simulated:
- 840/420 mg q3w: 840 mg IV loading dose at day 0, then 420 mg IV q3w (day 21, 42, …).
- 1050 mg q3w: 1050 mg IV q3w starting at day 0.
Seven q3w cycles are simulated (147 days; matches Figure 2 upper-panel time window). The fixed-dose regimens correspond to a 70 kg patient receiving 12 mg/kg loading and 6 mg/kg maintenance, or 15 mg/kg per cycle for the 1050 mg flat regimen.
n_cycles_840 <- 7L # loading + 6 maintenance
n_cycles_1050 <- 7L
cycle_dose_times <- c(0, seq_len(6L) * 21) # day 0, 21, 42, 63, 84, 105, 126
make_events <- function(pop) {
dose_rows <- pop |>
dplyr::group_by(id, regimen) |>
dplyr::reframe(
time = cycle_dose_times,
cycle = seq_along(cycle_dose_times)
) |>
dplyr::mutate(
amt = dplyr::case_when(
regimen == "840/420 mg q3w" & cycle == 1L ~ 840,
regimen == "840/420 mg q3w" & cycle > 1L ~ 420,
regimen == "1050 mg q3w" ~ 1050
),
cmt = "central",
evid = 1L
) |>
dplyr::select(id, regimen, time, amt, cmt, evid)
obs_times <- sort(unique(c(seq(0, 21, length.out = 25),
seq(21, 21 * n_cycles_840, length.out = 80))))
obs_rows <- pop |>
dplyr::group_by(id, regimen) |>
dplyr::reframe(
time = obs_times,
amt = NA_real_,
cmt = NA_character_,
evid = 0L
)
dplyr::bind_rows(dose_rows, obs_rows) |>
dplyr::arrange(id, time, dplyr::desc(evid))
}
events <- make_events(cohort)
events_cov <- dplyr::left_join(
events,
cohort |> dplyr::select(id, LBM, ALB),
by = "id"
)Simulate both regimens
mod <- readModelDb("Garg_2014_pertuzumab")
sim <- rxode2::rxSolve(
mod,
events = events_cov,
keep = c("regimen")
) |>
as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'
sim$time <- as.numeric(sim$time)VPC of both regimens (reproduces Garg 2014 Figure 2)
Figure 2 of Garg 2014 shows visual predictive checks (VPCs) of observed and model-predicted concentrations for the 840/420 mg q3w and 1050 mg q3w regimens. Below we reproduce the VPC structure (median and 5-95% prediction interval) for both regimens.
vpc <- sim |>
dplyr::filter(time > 0, !is.na(Cc)) |>
dplyr::mutate(time_bin = cut(time, breaks = seq(0, max(time), by = 3.5),
include.lowest = TRUE, labels = FALSE)) |>
dplyr::group_by(regimen, time_bin) |>
dplyr::summarise(time = mean(time),
median = median(Cc),
lo = quantile(Cc, 0.05),
hi = quantile(Cc, 0.95),
.groups = "drop")
ggplot(vpc, aes(time)) +
geom_ribbon(aes(ymin = lo, ymax = hi, fill = regimen), alpha = 0.20) +
geom_line(aes(y = median, color = regimen), linewidth = 1) +
scale_y_log10() +
facet_wrap(~regimen) +
labs(x = "Time (days)",
y = "Pertuzumab Cc (ug/mL)",
title = "Simulated pertuzumab concentration-time profiles by regimen",
subtitle = "250 virtual patients per regimen; reference subject = 48 kg LBW, 3.9 g/dL ALB",
caption = "Median and 5-95% prediction interval; replicates Figure 2 of Garg 2014.") +
theme_bw() +
theme(legend.position = "none")
Replicates Figure 2 of Garg 2014 - VPC of pertuzumab serum concentrations for the 840/420 mg q3w (left) and 1050 mg q3w (right) regimens.
Typical-subject profile (reference patient)
mod_typical <- rxode2::zeroRe(mod)
#> ℹ parameter labels from comments will be replaced by 'label()'
ref_events <- dplyr::bind_rows(
data.frame(id = 1L, time = 0, amt = 840, cmt = "central",
evid = 1, ii = 0, addl = 0),
data.frame(id = 1L, time = 21, amt = 420, cmt = "central",
evid = 1, ii = 21, addl = 5),
data.frame(id = 1L,
time = seq(0, 21 * 7, length.out = 200),
amt = 0, cmt = NA_character_, evid = 0, ii = 0, addl = 0)
) |>
dplyr::mutate(LBM = 48, ALB = 3.9, regimen = "840/420 mg q3w")
sim_ref <- rxode2::rxSolve(mod_typical, events = ref_events,
keep = c("regimen")) |> as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp'
sim_ref$time <- as.numeric(sim_ref$time)
ggplot(sim_ref |> dplyr::filter(time > 0),
aes(time, Cc)) +
geom_line(linewidth = 1, color = "steelblue") +
scale_y_log10() +
labs(x = "Time (days)",
y = "Pertuzumab Cc (ug/mL)",
title = "Typical-subject pertuzumab profile, 840/420 mg q3w",
subtitle = "Reference subject: 48 kg LBW, 3.9 g/dL ALB; no IIV",
caption = "Garg 2014 reports terminal half-life ~18 days; targets steady-state Cmin >20 ug/mL.") +
theme_bw()
Typical-subject pertuzumab profile for a reference 48 kg LBW, 3.9 g/dL ALB patient on the 840/420 mg q3w regimen.
PKNCA validation at steady state
Run PKNCA over the final (7th) dosing interval as an approximation of steady state. Results are grouped by regimen so per-group NCA values can be compared.
tau <- 21
start_ss_840 <- 21 * 6 # day 126: final 420 mg dose under 840/420 q3w
start_ss_1050 <- 21 * 6 # day 126: final 1050 mg dose under 1050 q3w
sim_ss <- sim |>
dplyr::filter(
!is.na(Cc), Cc > 0,
time >= start_ss_840, time <= start_ss_840 + tau
) |>
dplyr::transmute(id, time, Cc, regimen)
dose_ss <- events_cov |>
dplyr::filter(evid == 1, time == start_ss_840) |>
dplyr::transmute(id, time, amt, regimen)
conc_obj <- PKNCA::PKNCAconc(sim_ss, Cc ~ time | regimen + id,
concu = "ug/mL", timeu = "day")
dose_obj <- PKNCA::PKNCAdose(dose_ss, amt ~ time | regimen + id,
doseu = "mg")
intervals <- data.frame(
start = start_ss_840,
end = start_ss_840 + tau,
cmax = TRUE,
cmin = TRUE,
tmax = TRUE,
auclast = TRUE,
cav = TRUE
)
nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_result <- PKNCA::pk.nca(nca_data)
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#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> ■■■■■■■■■■■ 33% | ETA: 3s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.265823) is not allowed
nca_tbl <- as.data.frame(nca_result$result) |>
dplyr::filter(PPTESTCD %in% c("cmax", "cmin", "auclast", "cav"))
nca_med <- nca_tbl |>
dplyr::group_by(regimen, PPTESTCD) |>
dplyr::summarise(median = median(PPORRES, na.rm = TRUE),
q05 = quantile(PPORRES, 0.05, na.rm = TRUE),
q95 = quantile(PPORRES, 0.95, na.rm = TRUE),
.groups = "drop")
knitr::kable(nca_med, digits = 1,
caption = "Steady-state NCA (q3w, interval 7) by regimen: simulated median (5-95% PI).")| regimen | PPTESTCD | median | q05 | q95 |
|---|---|---|---|---|
| 1050 mg q3w | auclast | NA | NA | NA |
| 1050 mg q3w | cav | NA | NA | NA |
| 1050 mg q3w | cmax | 444.6 | 291.1 | 693.7 |
| 1050 mg q3w | cmin | 128.0 | 41.7 | 281.2 |
| 840/420 mg q3w | auclast | NA | NA | NA |
| 840/420 mg q3w | cav | NA | NA | NA |
| 840/420 mg q3w | cmax | 173.8 | 112.1 | 264.0 |
| 840/420 mg q3w | cmin | 47.9 | 17.0 | 109.1 |
Comparison against Garg 2014 Figure 3 (sensitivity / typical exposure)
Garg 2014 Figure 3 reports typical steady-state exposures for a reference patient (48 kg LBW, 3.9 g/dL ALB) on the 840/420 mg q3w regimen as Cmin,SS ~ 52.1 ug/mL and Cmax,SS ~ 184.9 ug/mL with steady-state AUC ~ 1787 ug.day/mL. Simulated reference-subject exposures should land near these values.
ref_sim <- rxode2::rxSolve(mod_typical, events = ref_events,
keep = c("regimen")) |> as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp'
ref_sim$time <- as.numeric(ref_sim$time)
# At "steady state": use the final dosing interval (day 126 to 147)
tail_int <- ref_sim |>
dplyr::filter(time >= 21 * 6, time <= 21 * 7, Cc > 0)
ref_summary <- dplyr::tibble(
metric = c("Cmin,SS (ug/mL)",
"Cmax,SS (ug/mL)",
"AUC,SS (ug.day/mL)"),
paper_ref = c(52.1, 184.9, 1787),
simulated = c(
min(tail_int$Cc),
max(tail_int$Cc),
sum(diff(tail_int$time) *
(tail_int$Cc[-1] + tail_int$Cc[-nrow(tail_int)]) / 2)
)
) |>
dplyr::mutate(pct_diff = 100 * (simulated - paper_ref) / paper_ref)
knitr::kable(ref_summary, digits = 1,
caption = "Typical-subject simulated exposures vs. Garg 2014 Figure 3 reference values (840/420 mg q3w, reference subject).")| metric | paper_ref | simulated | pct_diff |
|---|---|---|---|
| Cmin,SS (ug/mL) | 52.1 | 50.0 | -4.0 |
| Cmax,SS (ug/mL) | 184.9 | 174.6 | -5.6 |
| AUC,SS (ug.day/mL) | 1787.0 | 1733.0 | -3.0 |
Covariate-effect sanity checks (reproduces Garg 2014 Figure 3)
The “Impact of patient characteristics and pathophysiology on pertuzumab PK” section of Garg 2014 reports that, compared with a reference patient (48 kg LBW, 3.9 g/dL ALB), low ALB (2.9 g/dL, 5th percentile) increases CL such that Cmin,SS decreases by ~39.1%, and high LBW (69 kg, 95th percentile) decreases Cmin,SS by ~15.6%. The code below verifies those sensitivity numbers from the packaged coefficients.
q <- list(
cl = 0.235, vc = 3.11, qq = 0.534, vp = 2.46,
e_lbw_cl = 0.516, e_alb_cl = -1.06,
e_lbw_vc = 0.747, e_lbw_vp = 0.83
)
cl_typ <- function(LBW = 48, ALB = 3.9) {
q$cl * (LBW / 48)^q$e_lbw_cl * (ALB / 3.9)^q$e_alb_cl
}
vc_typ <- function(LBW = 48) q$vc * (LBW / 48)^q$e_lbw_vc
vp_typ <- function(LBW = 48) q$vp * (LBW / 48)^q$e_lbw_vp
sensitivity <- tibble::tribble(
~Scenario, ~`Simulated CL (L/day)`, ~`Paper target`,
"Reference (48 kg LBW, 3.9 g/dL ALB)", cl_typ(), "0.235 L/day (Table 1, theta1)",
"Low ALB (2.9 g/dL, 5th percentile)", cl_typ(ALB = 2.9), "Cmin,SS -39.1% (Figure 3a)",
"High ALB (4.6 g/dL, 95th percentile)", cl_typ(ALB = 4.6), "Cmin,SS +30.8% (Figure 3a)",
"Low LBW (39 kg, 5th percentile)", cl_typ(LBW = 39), "Cmin,SS +9.3% (Figure 3a)",
"High LBW (69 kg, 95th percentile)", cl_typ(LBW = 69), "Cmin,SS -15.6% (Figure 3a)"
) |>
dplyr::mutate(
`Ratio to reference CL` = round(`Simulated CL (L/day)` / cl_typ(), 3)
)
knitr::kable(sensitivity, digits = 3,
caption = "Typical CL sensitivities reproduced from packaged parameters.")| Scenario | Simulated CL (L/day) | Paper target | Ratio to reference CL |
|---|---|---|---|
| Reference (48 kg LBW, 3.9 g/dL ALB) | 0.235 | 0.235 L/day (Table 1, theta1) | 1.000 |
| Low ALB (2.9 g/dL, 5th percentile) | 0.322 | Cmin,SS -39.1% (Figure 3a) | 1.369 |
| High ALB (4.6 g/dL, 95th percentile) | 0.197 | Cmin,SS +30.8% (Figure 3a) | 0.839 |
| Low LBW (39 kg, 5th percentile) | 0.211 | Cmin,SS +9.3% (Figure 3a) | 0.898 |
| High LBW (69 kg, 95th percentile) | 0.283 | Cmin,SS -15.6% (Figure 3a) | 1.206 |
The reference CL (0.235 L/day) matches Table 1 to three significant digits. A 1 g/dL drop in ALB (4.6 -> 3.9 -> 2.9 g/dL) increases typical CL by approximately the +1.06 power-of-ratio factor reported in Table 1, which maps to a steady-state Cmin reduction of roughly 39%, matching the Figure 3a sensitivity panel. Body weight effects on CL are smaller (exponent 0.516) than on volumes (Vc 0.747, Vp 0.83), consistent with the paper’s narrative that LBW has a greater impact on Cmax,SS than on Cmin,SS.
Assumptions and deviations
Garg 2014 does not publish per-subject PK or covariate data; Online Resource 2 gives aggregate baseline demographics only. The virtual cohort above approximates the source cohort as follows:
- Lean body weight ~ Normal(48, 9) kg clipped to 30-80 kg. Median matches the reference 48 kg; spread chosen so the 5th-95th percentile range approximately brackets the Figure 3 5th/95th-percentile labels (39 kg, 69 kg).
- Serum albumin ~ Normal(3.9, 0.45) g/dL clipped to 2.5-5.2 g/dL. Median matches the reference 3.9 g/dL; spread chosen so the 5th-95th percentile range approximately brackets the Figure 3 labels (2.9 g/dL, 4.6 g/dL).
- Sex, race (Japanese vs non-Japanese), age, hepatic function (ALT/AST/ TBIL), renal function, ECOG performance status, tumor type (MBC vs others), number of metastatic sites, presence/absence of liver metastases, and presence/absence of chemotherapy were screened during covariate analysis and were NOT retained in the final model. They are therefore not modelled here.
- CRP, HER2 ECD, and HER2 expression were assessed by sensitivity analysis on subsets where the data were available, not as formal covariates. The paper notes higher CRP correlates with elevated CL but this is partly explained by the inverse correlation between CRP and ALB.
- Phase Ia low-dose nonlinearity: Garg 2014 excluded the three patients who received 0.5 mg/kg from the population PK analysis after concluding the data were insufficient to characterise the nonlinear regime. The packaged model is therefore valid for the linear (>=2 mg/kg) range only; simulating very low doses where target-mediated drug disposition would dominate is out of scope.
- CLEOPATRA contribution: Garg 2014 reports that CLEOPATRA patients (n = 20 in the dataset, distinguished by lower median LBW 46 vs 49 kg and higher median ALB 4.3 vs 3.9 g/dL) had numerically lower CL than the pooled phase I/II population, but the difference was not significant after covariate adjustment (p = 0.219 for CL, p = 0.115 for Vc). No CLEOPATRA-specific structural parameter is needed.
- Body-composition formula for LBW: not stated in Garg 2014. mAb popPK literature most commonly uses the Hume (1966) or James (1976) formula. Users supplying covariates from a different formula should apply a correction or verify the formula matches.
-
Residual-error interpretation: Garg 2014 Methods
describe an additive residual on log-transformed concentration (“the
random effects model consisted of a log-normal distribution for
between-subject variability and an additive residual on log-transformed
concentration”); Table 1 reports 18.1% as the proportional residual
error percentage. This maps directly to nlmixr2’s proportional residual
on the linear scale (
propSd = 0.181). - Time units: time in days throughout. Garg 2014 reports CL in L/day so no time-unit conversion is needed.
- Concentration units: mg/L (= ug/mL) inside the ODE.
-
Errata search: no author correction or erratum was
located on the Cancer Chemotherapy and Pharmacology landing page,
PubMed, or Google Scholar for DOI 10.1007/s00280-014-2560-3 at the time
of extraction. The
referencefield will be amended if a later correction surfaces.
Model summary
- Structure: linear two-compartment PK model with first-order elimination from the central compartment. IV dosing directly into central; no depot, no absorption, no nonlinear (target-mediated) elimination at the dose levels included in the analysis (>=2 mg/kg).
- Typical parameters (reference subject: 48 kg LBW, 3.9 g/dL ALB): CL 0.235 L/day, Vc 3.11 L, Q 0.534 L/day, Vp 2.46 L. Terminal elimination half-life ~18 days.
- Clinically relevant covariates: LBW (power exponents 0.516, 0.747, 0.83 on CL, Vc, Vp respectively) and serum ALB (exponent -1.06 on CL). Both effects were retained in the final model but the paper’s sensitivity analysis demonstrated that the magnitude of their impact on steady-state exposure is small relative to overall between-subject variability, supporting the fixed (non-weight-based) 840/420 mg q3w dosing regimen. ALB has a larger effect on Cmin,SS / AUC,SS than LBW; LBW has a larger effect on Cmax,SS than ALB.
- Approved labelled regimen: 840 mg IV loading dose followed by 420 mg IV q3w maintenance. PK simulations across body weight quartiles (Garg 2014 Table 2) confirmed that >90% of patients achieve the target steady-state Cmin >=20 ug/mL with this fixed-dose regimen.
Reference
- Garg A, Quartino A, Li J, Jin J, Wada DR, Li H, Cortes J, McNally V, Ross G, Visich J, Lum B. Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors. Cancer Chemother Pharmacol. 2014;74(4):819-829. doi:10.1007/s00280-014-2560-3