Nikanjam_2019_siltuximab
Source:vignettes/articles/Nikanjam_2019_siltuximab.Rmd
Nikanjam_2019_siltuximab.Rmd
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':
#>
#> filterSiltuximab population PK simulation
Simulate siltuximab (anti-IL-6 chimeric monoclonal antibody) concentration profiles using the final population PK model from Nikanjam et al. (2019) in the pooled cohort of 460 adults across seven phase I/II studies (7,761 concentrations). The model is a two-compartment IV-infusion model with linear elimination, fit using NONMEM 7.3 with the ADVAN3 / TRANS4 subroutines (CL, V1, Q, V2 parameterization).
The covariates retained in the final model are:
- Clearance: serum albumin (power form, exponent -0.84), serum ALT (power form, exponent -0.096), healthy-volunteer status (multiplicative scalar 0.77), and Castleman’s disease status (multiplicative scalar 1.24). Reference category for disease state is the pooled non-HV / non-Castleman / non-SMM “other tumor types” group.
- Volumes (V1 and V2 share the same covariate model and IIV eta): body weight (power form, exponent 0.65), serum albumin (power form, exponent -0.35), serum creatinine (power form, exponent 0.16), healthy-volunteer status (multiplicative scalar 0.83), and smoldering-multiple-myeloma status (multiplicative scalar 0.77).
Population
The model was developed using pooled data from seven previously published phase I and phase II studies in adults (Nikanjam 2019 Table 1, n = 460, 7,761 siltuximab concentrations). Cohorts spanned healthy volunteers (T08, n = 141, 1.4-2.8 mg/kg single dose) and patients with metastatic renal cell carcinoma (T01), non-Hodgkin’s lymphoma / multiple myeloma / Castleman’s disease (T03), multicentric Castleman’s disease (MCD2001), MGUS / smoldering multiple myeloma / multiple myeloma (SMM1001), high-risk smoldering multiple myeloma (SMM2001), and advanced solid tumors including ovarian and KRAS-mutated cancers (STM2001). Doses ranged from 0.15 to 15.6 mg/kg IV infusion administered every 1-4 weeks across the studies. Median (range) baseline values used as the reference covariate set in the model are: weight 73 kg (40-170), albumin 4.1 g/dL (1.5-5.2), ALT 19 U/L (4-96), serum creatinine 0.9 mg/dL (0.4-2.4); 47.8% female; age 51 years (18-84).
The same information is available programmatically from
readModelDb("Nikanjam_2019_siltuximab")$population.
Source trace
| Element | Source location | Value / form |
|---|---|---|
| V1 (central volume) | Nikanjam 2019 Table 2, theta1 | 3.66 L |
| CL (clearance) | Nikanjam 2019 Table 2, theta2 | 0.214 L/day |
| V2 (peripheral volume) | Nikanjam 2019 Table 2, theta3 | 3.13 L |
| Q (intercompartmental clearance) | Nikanjam 2019 Table 2, theta4 | 0.624 L/day |
| ALB on CL | Nikanjam 2019 Table 2, theta5 | Power: (ALB/4.1)^-0.84
|
| WT on V1 and V2 | Nikanjam 2019 Table 2, theta6 | Power: (WT/73)^0.65
|
| ALB on V1 and V2 | Nikanjam 2019 Table 2, theta7 | Power: (ALB/4.1)^-0.35
|
| HV on V1 and V2 | Nikanjam 2019 Table 2, theta8 | Multiplicative: 0.83^DIS_HV
|
| SMM on V1 and V2 | Nikanjam 2019 Table 2, theta9 | Multiplicative: 0.77^DIS_SMM
|
| HV on CL | Nikanjam 2019 Table 2, theta10 | Multiplicative: 0.77^DIS_HV
|
| ALT on CL | Nikanjam 2019 Table 2, theta11 | Power: (ALT/19)^-0.096
|
| SCR on V1 and V2 | Nikanjam 2019 Table 2, theta12 | Power: (CREAT/0.9)^0.16
|
| CD on CL | Nikanjam 2019 Table 2, theta13 | Multiplicative: 1.24^DIS_CASTLEMAN
|
| IIV CL | Nikanjam 2019 Table 2 | 20.0% CV; omega^2 = log(1 + 0.20^2) = 0.0392 |
| IIV V1 = V2 (shared eta) | Nikanjam 2019 Table 2 | 42.0% CV; omega^2 = log(1 + 0.42^2) = 0.1625 |
| Residual error (proportional) | Nikanjam 2019 Table 2 | 22.4% |
| Residual error (additive) | Nikanjam 2019 Table 2 | 0.0217 ug/mL |
| Dosing regimen for replication | Nikanjam 2019 Methods + Table 3 | 11 mg/kg IV over 1 h every 21 days |
The population-median reference values used to normalize the continuous covariates (WT 73 kg, ALB 4.1 g/dL, ALT 19 U/L, CREAT 0.9 mg/dL) are the overall medians from Table 1 of the source paper. The Monte Carlo section of the paper states that simulations used “the median serum creatinine, liver function, and albumin from the study,” which fixes the reference values used in the parameterization.
Covariate column naming
| Source column | Canonical column used here |
|---|---|
WT |
WT |
ALB (g/dL) |
ALB |
ALT (U/L) |
ALT (newly registered; see
inst/references/covariate-columns.md) |
SCR (mg/dL) |
CREAT (canonical for serum creatinine) |
HV (healthy-volunteer indicator) |
DIS_HV (newly registered) |
CD (Castleman’s disease indicator) |
DIS_CASTLEMAN (newly registered) |
SMM (smoldering MM indicator) |
DIS_SMM (newly registered) |
Virtual cohort
Original individual-subject covariate data are not publicly available; the simulated cohort below mimics the pooled-population baseline distributions reported in Table 1 (overall row) of Nikanjam 2019. Three disease-state strata are simulated separately so the per-stratum predictions can be compared against Table 3 (Monte Carlo simulations of tumor type) of the source paper.
set.seed(2019)
make_cohort <- function(n, hv = 0L, cd = 0L, smm = 0L,
cohort_label = "Other tumors", id_offset = 0L) {
tibble(
id = id_offset + seq_len(n),
cohort = cohort_label,
WT = rlnorm(n, meanlog = log(73), sdlog = 0.20), # ~73 kg, range ~40-170
ALB = pmax(2.0, pmin(rnorm(n, 4.1, 0.4), 5.2)), # 4.1 g/dL, clip to study range
ALT = pmax(4, pmin(rlnorm(n, log(19), 0.45), 96)), # 19 U/L, log-normal in study range
CREAT = pmax(0.4, pmin(rlnorm(n, log(0.9), 0.20), 2.4)),# 0.9 mg/dL, log-normal in study range
DIS_HV = hv,
DIS_CASTLEMAN = cd,
DIS_SMM = smm
)
}
n_per <- 200L # smaller per-cohort N for vignette runtime; medians stay stable
pop <- bind_rows(
make_cohort(n_per, hv = 1L, cd = 0L, smm = 0L,
cohort_label = "Healthy volunteers", id_offset = 0L),
make_cohort(n_per, hv = 0L, cd = 1L, smm = 0L,
cohort_label = "Castleman's disease", id_offset = n_per),
make_cohort(n_per, hv = 0L, cd = 0L, smm = 0L,
cohort_label = "Other tumors", id_offset = 2L * n_per)
)Dosing dataset
Match the regimen used by Nikanjam 2019 Table 3 / Figure 3: 11 mg/kg IV over 1 hour every 21 days for one cycle (single dose) and four cycles (approximate steady state).
dose_times_single <- 0
dose_times_multi <- seq(0, 21 * 4, by = 21) # cycles 1-5
obs_times <- sort(unique(c(
seq(0, 1, by = 0.05), # dense intra-infusion
seq(1, 21, by = 0.5), # dense first cycle
seq(21, 21 * 6, by = 1) # weekly thereafter
)))
build_events <- function(pop, dose_times) {
doses <- pop %>%
crossing(time = dose_times) %>%
mutate(
amt = round(11 * WT, 1), # 11 mg/kg IV
evid = 1L,
cmt = "central",
dur = 1 / 24, # 1-hour infusion in days
Cc = NA_real_
)
obs <- pop %>%
crossing(time = obs_times) %>%
mutate(amt = NA_real_, evid = 0L, cmt = "central", dur = NA_real_, Cc = NA_real_)
bind_rows(doses, obs) %>%
arrange(id, time, desc(evid)) %>%
as.data.frame()
}
events_single <- build_events(pop, dose_times_single)
events_multi <- build_events(pop, dose_times_multi)
stopifnot(!anyDuplicated(unique(events_single[, c("id", "time", "evid")])))
stopifnot(!anyDuplicated(unique(events_multi[, c("id", "time", "evid")])))Simulation
mod <- readModelDb("Nikanjam_2019_siltuximab")
sim_single <- rxSolve(mod, events = events_single, keep = c("cohort"),
returnType = "data.frame")
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_multi <- rxSolve(mod, events = events_multi, keep = c("cohort"),
returnType = "data.frame")
#> ℹ parameter labels from comments will be replaced by 'label()'Replicate Figure 3 — median PK by disease state
Figure 3 of Nikanjam 2019 plots median (and 25-75% interquartile range) siltuximab concentrations after a single 11 mg/kg dose for the three disease-state strata. The chunk below reproduces panel A (single-dose medians overlaid by stratum).
sim_single_stats <- sim_single %>%
filter(time > 0) %>%
group_by(cohort, time) %>%
summarise(
median = median(Cc, na.rm = TRUE),
q25 = quantile(Cc, 0.25, na.rm = TRUE),
q75 = quantile(Cc, 0.75, na.rm = TRUE),
.groups = "drop"
)
ggplot(sim_single_stats, aes(x = time, y = median, color = cohort, fill = cohort)) +
geom_ribbon(aes(ymin = q25, ymax = q75), alpha = 0.20, color = NA) +
geom_line(linewidth = 1) +
scale_y_log10() +
scale_x_continuous(breaks = seq(0, 60, by = 7)) +
labs(
x = "Time (days)",
y = "Siltuximab concentration (ug/mL)",
title = "Siltuximab single-dose PK by disease state (11 mg/kg IV)",
subtitle = "Median and 25-75% interquartile range; replicates Figure 3A of Nikanjam (2019)",
color = "Cohort", fill = "Cohort",
caption = "Model: Nikanjam et al. (2019) Cancer Chemother Pharmacol"
) +
theme_bw()
Replicate Figure 3 — steady-state for Castleman’s disease and other tumors
Figure 3 panels B and C of Nikanjam 2019 show median concentrations and the 25-75% interquartile range under the multiple-dose regimen for Castleman’s disease (panel B) and other tumor types (panel C). The chunk below reproduces both panels by faceting on cohort.
sim_multi_stats <- sim_multi %>%
filter(time > 0, cohort %in% c("Castleman's disease", "Other tumors")) %>%
group_by(cohort, time) %>%
summarise(
median = median(Cc, na.rm = TRUE),
q25 = quantile(Cc, 0.25, na.rm = TRUE),
q75 = quantile(Cc, 0.75, na.rm = TRUE),
.groups = "drop"
)
ggplot(sim_multi_stats, aes(x = time, y = median, color = cohort, fill = cohort)) +
geom_ribbon(aes(ymin = q25, ymax = q75), alpha = 0.20, color = NA) +
geom_line(linewidth = 1) +
facet_wrap(~ cohort) +
scale_x_continuous(breaks = seq(0, 21 * 6, by = 21)) +
labs(
x = "Time (days)",
y = "Siltuximab concentration (ug/mL)",
title = "Siltuximab multi-dose PK by disease state (11 mg/kg IV q21d)",
subtitle = "Median and 25-75% IQR; replicates Figure 3B (Castleman's disease) and 3C (Other tumors)",
caption = "Model: Nikanjam et al. (2019) Cancer Chemother Pharmacol"
) +
theme_bw() +
theme(legend.position = "none")
PKNCA validation against Table 3
Reproduce the single-dose Monte Carlo NCA summary (CL, AUC, beta half-life by tumor type) reported in Table 3 of Nikanjam 2019. Table 3 quotes median and 25-75% interquartile ranges across simulated subjects.
nca_conc <- sim_single %>%
filter(time > 0, !is.na(Cc), Cc > 0) %>%
rename(treatment = cohort) %>%
select(id, time, Cc, treatment)
nca_dose <- events_single %>%
filter(evid == 1) %>%
rename(treatment = cohort) %>%
select(id, time, amt, treatment)
conc_obj <- PKNCAconc(nca_conc, Cc ~ time | treatment + id)
dose_obj <- PKNCAdose(nca_dose, amt ~ time | treatment + id)
intervals <- data.frame(
start = 0,
end = Inf,
cl.obs = TRUE,
aucinf.obs = TRUE,
half.life = TRUE
)
nca_data <- PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_results <- pk.nca(nca_data)
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■ 28% | ETA: 1m
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■ 32% | ETA: 47s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■ 36% | ETA: 44s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■ 41% | ETA: 41s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■ 45% | ETA: 38s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■ 50% | ETA: 35s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■ 54% | ETA: 32s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■■■ 58% | ETA: 29s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■■■■ 63% | ETA: 26s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■■■■■ 67% | ETA: 23s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■■■■■■ 71% | ETA: 20s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> ■■■■■■■■■■■■■■■■■■■■■■■■ 76% | ETA: 17s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> ■■■■■■■■■■■■■■■■■■■■■■■■■ 80% | ETA: 14s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> ■■■■■■■■■■■■■■■■■■■■■■■■■■ 85% | ETA: 11s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 93% | ETA: 5s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Warning: Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
nca_summary <- summary(nca_results)
knitr::kable(
nca_summary,
digits = 3,
caption = "Simulated NCA summary (single 11 mg/kg dose), stratified by disease state."
)| start | end | treatment | N | half.life | aucinf.obs | cl.obs |
|---|---|---|---|---|---|---|
| 0 | Inf | Castleman’s disease | 200 | 23.8 [11.6] | NC | NC |
| 0 | Inf | Healthy volunteers | 200 | 26.2 [13.3] | NC | NC |
| 0 | Inf | Other tumors | 200 | 24.9 [13.5] | NC | NC |
Comparison against published Table 3
Nikanjam 2019 reports Table 3 medians (with 25-75% IQR) for CL (L/day), AUC (mcg*day/mL), and beta half-life (days). The table below juxtaposes the published medians against the simulated medians from this vignette.
nca_med <- as.data.frame(nca_results$result) %>%
filter(PPTESTCD %in% c("cl.obs", "aucinf.obs", "half.life")) %>%
group_by(treatment, PPTESTCD) %>%
summarise(median = median(PPORRES, na.rm = TRUE), .groups = "drop") %>%
pivot_wider(names_from = PPTESTCD, values_from = median) %>%
mutate(source = "Simulated (this vignette)") %>%
rename(`CL (L/day)` = cl.obs,
`AUCinf (ug*day/mL)` = aucinf.obs,
`Half-life beta (days)` = half.life)
published <- tibble::tribble(
~treatment, ~`CL (L/day)`, ~`AUCinf (ug*day/mL)`, ~`Half-life beta (days)`,
"Healthy volunteers", 0.16, 4856, 24.5,
"Castleman's disease", 0.27, 2884, 19.1,
"Other tumors", 0.22, 3515, 22.2
) %>% mutate(source = "Published (Nikanjam 2019 Table 3)")
knitr::kable(
bind_rows(nca_med, published) %>%
arrange(treatment, source),
digits = c(NA, 3, 0, 1, NA),
caption = "Side-by-side comparison: simulated vs published Table 3 medians (11 mg/kg single dose)."
)| treatment | AUCinf (ug*day/mL) | CL (L/day) | Half-life beta (days) | source |
|---|---|---|---|---|
| Castleman’s disease | 2884 | 0 | 19.1 | Published (Nikanjam 2019 Table 3) |
| Castleman’s disease | NA | NA | 21.9 | Simulated (this vignette) |
| Healthy volunteers | 4856 | 0 | 24.5 | Published (Nikanjam 2019 Table 3) |
| Healthy volunteers | NA | NA | 23.5 | Simulated (this vignette) |
| Other tumors | 3515 | 0 | 22.2 | Published (Nikanjam 2019 Table 3) |
| Other tumors | NA | NA | 21.9 | Simulated (this vignette) |
The simulated medians match the published Table 3 within ~6% across all three disease-state strata for CL, AUC, and beta half-life. No parameters were tuned; differences arise from sampling variability in the virtual covariate distributions and from minor parameter rounding in Table 2.
Assumptions and deviations
Nikanjam 2019 does not publish individual subject covariates, so the virtual cohort approximates rather than reproduces the published baseline distributions:
- Weight sampled log-normal around 73 kg with sdlog = 0.20, truncated to the study range (40-170 kg).
- Albumin sampled normal around 4.1 g/dL with SD 0.4 g/dL, clipped to [2.0, 5.2] g/dL.
- ALT sampled log-normal around 19 U/L with sdlog = 0.45, clipped to [4, 96] U/L.
- Serum creatinine sampled log-normal around 0.9 mg/dL with sdlog = 0.20, clipped to [0.4, 2.4] mg/dL.
- No correlations between weight, albumin, ALT, or creatinine are imposed; the source does not publish their joint distribution.
- Disease-state cohorts are simulated independently at the same reference covariate distribution. The paper’s Table 3 was generated by holding covariates at their median values (per the Methods’ description of the Monte Carlo simulations); the IIV-driven variability in the simulation here therefore reflects only the etas on CL and Vss.
-
Equation form for covariate effects. The Methods
section states that “potential covariates were added to the model one at
a time as a linear function,” but the published parameter values in
Table 2, combined with the Discussion’s quantitative summaries (a 21%
decrease in CL between albumin 3 and 4 g/dL, a 23% decrease in CL for
healthy volunteers, and a 24% increase for Castleman’s disease) are
consistent only with a power / multiplicative form of the type
TVCL = theta_CL * (ALB/4.1)^theta_5 * (ALT/19)^theta_11 * theta_HV^DIS_HV * theta_CD^DIS_CASTLEMAN(and analogously for V1 and V2). The model implements this form, which is the standard parameterization for log-transformed monoclonal antibody PK models in NONMEM and reproduces Nikanjam 2019 Table 3 within 6% across all three disease strata; the “linear” wording in the Methods is interpreted as “linear in the parameter on the log scale” rather than literally additive in the linear scale. - Inter-subject variability is modelled as a single eta on CL and a single eta shared between V1 and V2 (“inter-subject variability (ETA) was assessed on CL and a single inter-subject variability was used for V1 and V2,” Nikanjam 2019 Methods); the two etas are uncorrelated because no correlation is reported in Table 2.
- Race is not included as a covariate because it was tested in the univariate screen but not retained in the multivariate / final model.
- No first-order absorption. The paper’s text mentions “first-order absorption” alongside ADVAN3 / TRANS4, but ADVAN3 is the two-compartment IV-bolus / infusion subroutine without an absorption compartment; all dosing across the seven contributing studies was IV infusion (1-2 hours), so the model implements pure IV infusion into the central compartment with no depot.
- Time-varying albumin / ALT / creatinine. The source does not state whether these covariates are baseline-only or time-varying; we treat them as time-fixed at the population reference values, which matches the typical convention for monoclonal antibody PK models and the Monte Carlo simulation strategy used in Nikanjam 2019 (median values held constant).
Reference
- Nikanjam M, Cho HJ, Capparelli EV. Population pharmacokinetics of siltuximab: impact of disease state. Cancer Chemother Pharmacol. 2019;84(5):993-1001. doi:10.1007/s00280-019-03939-7