Raltegravir (Wang 2011)
Source:vignettes/articles/Wang_2011_raltegravir.Rmd
Wang_2011_raltegravir.RmdModel and source
- Citation: Wang L, Soon GH, Seng KY, Li J, Lee E, Yong EL, Goh BC, Flexner C, Lee L. Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers. Antimicrobial Agents and Chemotherapy. 2011 Sep;55(9):4090-4095. doi:10.1128/AAC.00593-11.
- Description: Population PK model for plasma and intracellular (PBMC)
raltegravir after a single 400 mg oral dose in six healthy male
Singaporean volunteers (Wang 2011). Plasma PK is described by a
one-compartment model with first-order elimination preceded by a chain
of two transit compartments between depot and central (Kappelhoff 2005
transit-absorption parameterisation: MAT = (n + 1) / ktr with n = 2
transit compartments). Bioavailability F is implicit in the apparent
CL/F and V/F. Intracellular (PBMC) raltegravir is described as an
empirical partition of the predicted plasma concentration via the
paper’s accumulation ratio ACR (point estimate 11.2%) with its own
inter-individual variability and exponential residual error (Wang 2011
Eq.: C_IC,obs = ACR * C_plasma,pred * exp(eps_IC)). The packaged model
maps ACR to the canonical paper-named bare parameter
fracand its log-transformed primarylfrac. No baseline covariates were retained in the final model. Note that the paper’s term ‘accumulation ratio’ is a misnomer in the conventional sense – ACR < 1 means raltegravir does NOT accumulate intracellularly, consistent with simple diffusion of unbound drug into PBMCs (the authors’ Conclusions). - Article: https://doi.org/10.1128/AAC.00593-11
Wang 2011 was a pilot pharmacokinetic study of a single 400 mg oral raltegravir dose in six healthy male Singaporean volunteers, designed to determine whether sustained antiviral efficacy in plasma-PK-variable HIV patients could be explained by intracellular drug accumulation in peripheral blood mononuclear cells (PBMCs). The population PK model links plasma and intracellular concentrations through a simple empirical accumulation ratio (ACR) of 11.2%, supporting the authors’ conclusion that raltegravir does NOT accumulate intracellularly and that PBMC concentrations can be predicted from plasma data by simple multiplicative scaling.
Population
Six healthy adult male volunteers were enrolled in Singapore (single centre, National University Health System). Their median weight was 67.4 kg (range 56.5 to 87.1 kg) and median age 33.5 years (range 31 to 36). All subjects fasted overnight and received a single 400 mg oral dose of raltegravir on day 1 at 8 a.m. Inclusion criteria required smoking less than 10 cigarettes per day, hemoglobin > 10.9 g/dl, platelet count >= 125,000/mm^3, creatinine clearance >= 60 mL/min, and lipase or amylase < 1.1x ULN.
Paired blood samples for plasma and PBMCs were collected predose and at 4, 8, 12, 24, and 48 h post-dose; additional plasma-only samples were collected at 0.5, 1, 1.5, 2, 3, 5, 6, and 10 h. PBMC concentrations were computed assuming a cell volume of 0.4 pL.
Programmatic access:
mod_meta <- readModelDb("Wang_2011_raltegravir")()$meta
mod_meta$population
#> $species
#> [1] "human"
#>
#> $n_subjects
#> [1] 6
#>
#> $n_studies
#> [1] 1
#>
#> $age_range
#> [1] "31-36 years"
#>
#> $age_median
#> [1] "33.5 years"
#>
#> $weight_range
#> [1] "56.5-87.1 kg"
#>
#> $weight_median
#> [1] "67.4 kg"
#>
#> $sex_female_pct
#> [1] 0
#>
#> $disease_state
#> [1] "Healthy male volunteers (HIV-negative). Inclusion required smoking <10 cigarettes/day, hemoglobin >10.9 g/dl, platelet count >=125,000/mm^3, creatinine clearance >=60 mL/min, and lipase or pancreatic amylase <1.1 x upper limit of normal. Subjects on any concomitant medication beyond aspirin / acetaminophen / chlorpheniramine / multivitamins were excluded."
#>
#> $dose_range
#> [1] "Single 400 mg raltegravir orally with water under fasted conditions on study day 1. Paired blood samples for plasma and PBMC were collected predose (0 h) and at 4, 8, 12, 24, and 48 h post-dose; additional plasma samples were collected at 0.5, 1, 1.5, 2, 3, 5, 6, and 10 h post-dose. PBMC concentrations were computed assuming a cell volume of 0.4 pL."
#>
#> $regions
#> [1] "Singapore (single centre, National University Health System)"
#>
#> $age_eligibility
#> [1] "21-65 years"
#>
#> $notes
#> [1] "Baseline demographics from Wang 2011 Results, 'Study population and safety' (page 4090) and 'Pharmacokinetic parameters' (page 4091). Final population pharmacokinetic estimates are reported in Table 1 of the source. The visual predictive checks based on 500 simulated profiles (Wang 2011 Fig. 4) covered 97% of the observed concentrations within the 95% prediction interval."Source trace
Per-parameter origin is recorded as an in-file comment next to each
ini() entry in
inst/modeldb/specificDrugs/Wang_2011_raltegravir.R. The
table below collects them in one place.
| Equation / parameter | Value | Source location |
|---|---|---|
| MAT | 0.887 h | Wang 2011 Table 1, Mean absorption time (RSE 27.6%) |
| n transit | 2 (structural; fixed) | Wang 2011 Table 1, Number of transition compartments |
| CL/F | 39.1 L/h | Wang 2011 Table 1, Clearance/bioavailability (RSE 20.8%) |
| V/F | 272 L | Wang 2011 Table 1, Volume distribution/bioavailability (RSE 21.8%) |
| ACR | 0.112 | Wang 2011 Table 1, Accumulation ratio = 11.2% (RSE 35%) |
| IIV in MAT | 66.2% CV | Wang 2011 Table 1, IIV in MAT (RSE 52.5%) |
| IIV in CL/F | 56.4% CV | Wang 2011 Table 1, IIV in CL/F (RSE 28.6%) |
| IIV in V/F | 56.7% CV | Wang 2011 Table 1, IIV in V/F (RSE 24.6%) |
| IIV in ACR | 104% CV | Wang 2011 Table 1, IIV in accumulation ratio (RSE 55.6%) |
| Correlation CL/F~V/F | 0.559 | Wang 2011 Table 1, Correlation between CL/F and V/F (RSE 24.6%) |
| Exp. error plasma | 86.7% (= sigma on log) | Wang 2011 Table 1, Exponential error of plasma concns (RSE 15.4%) |
| Exp. error IC | 64.9% (= sigma on log) | Wang 2011 Table 1, Exponential error of intracellular concns (RSE 51.1%) |
| Transit-chain ktr | 3 / MAT (derived) | Wang 2011 Methods page 4091, MAT = (n+1)/ktr formula |
| Plasma ODE chain | depot -> T1 -> T2 -> central | Wang 2011 Fig. 1, Basic population PK model |
| Intracellular model | C_IC,obs = ACR * C_plasma * exp(eps) | Wang 2011 Methods page 4091, intracellular partition equation |
CV values are converted to internal log-scale variances using
omega^2 = log(1 + CV^2). The CL/F~V/F covariance is
0.559 * sqrt(omega^2_lcl * omega^2_lvc) = 0.155.
Molecular-weight unit conversion
Wang 2011 reports concentrations and AUC values in nmol/L (the units
of HIV-1 integrase IC50). The packaged model uses mass-balanced mg /
mg/L (matching Lee_2016_raltegravir). Conversions for
cross-checking against the paper’s NCA table use raltegravir molecular
weight 444.42 g/mol:
mw_ral <- 444.42 # g/mol
nm_to_mgL <- function(nm) nm * mw_ral * 1e-6 # nmol/L -> mg/L
nmh_to_mghL <- function(nmh) nmh * mw_ral * 1e-6 # nmol*h/L -> mg*h/L
# Published geometric-mean NCA (Wang 2011 Table; Pharmacokinetic parameters)
paper_nca <- tibble::tribble(
~param, ~unit_paper, ~value_paper, ~value_mgL,
"Plasma Cmax", "nmol/L", 2246, nm_to_mgL(2246),
"Plasma AUC0-12", "nmol*h/L", 10776, nmh_to_mghL(10776),
"Plasma AUC0-inf", "nmol*h/L", 13119, nmh_to_mghL(13119),
"Plasma C12", "nmol/L", 338.7, nm_to_mgL(338.7),
"Plasma half-life (NCA)", "h", 7.8, NA,
"Intracellular Cmax", "nmol/L", 383, nm_to_mgL(383),
"Intracellular AUC0-12", "nmol*h/L", 2073, nmh_to_mghL(2073),
"Intracellular AUC0-inf", "nmol*h/L", 2435, nmh_to_mghL(2435),
"IC half-life (NCA)", "h", 4.5, NA
)
knitr::kable(paper_nca, digits = 4,
caption = "Geometric-mean NCA values from Wang 2011 (Pharmacokinetic parameters paragraph), shown in the paper's nmol/L units and as the equivalent mg/L used by the packaged model.")| param | unit_paper | value_paper | value_mgL |
|---|---|---|---|
| Plasma Cmax | nmol/L | 2246.0 | 0.9982 |
| Plasma AUC0-12 | nmol*h/L | 10776.0 | 4.7891 |
| Plasma AUC0-inf | nmol*h/L | 13119.0 | 5.8303 |
| Plasma C12 | nmol/L | 338.7 | 0.1505 |
| Plasma half-life (NCA) | h | 7.8 | NA |
| Intracellular Cmax | nmol/L | 383.0 | 0.1702 |
| Intracellular AUC0-12 | nmol*h/L | 2073.0 | 0.9213 |
| Intracellular AUC0-inf | nmol*h/L | 2435.0 | 1.0822 |
| IC half-life (NCA) | h | 4.5 | NA |
Virtual cohort
Original observed data are not publicly available. The figures below use a virtual population with the published Wang 2011 covariate distribution (six healthy adult males, all in their early thirties, roughly two-thirds of subjects between 60 and 75 kg, no other covariates retained in the final model).
set.seed(202611)
n_sub <- 200L
events <- data.frame(
id = seq_len(n_sub),
time = 0,
amt = 400,
cmt = "depot",
evid = 1L
)
times <- sort(unique(c(0,
seq(0.25, 12, by = 0.25),
seq(13, 24, by = 1),
seq(28, 48, by = 4),
c(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48))))
obs_plasma <- expand.grid(id = seq_len(n_sub), time = times)
obs_plasma$amt <- NA_real_
obs_plasma$cmt <- "Cc"
obs_plasma$evid <- 0L
obs_ic <- obs_plasma
obs_ic$cmt <- "Cic"
events <- dplyr::bind_rows(events, obs_plasma, obs_ic)
events <- events[order(events$id, events$time, events$evid > 0), ]Simulation
mod <- readModelDb("Wang_2011_raltegravir")
# rxSolve produces one row per (id, time, dvid). Since Cc and Cic are
# both computed as derived model variables on every row, each row carries
# both columns -- we deduplicate to one row per (id, time) for plotting
# and NCA.
sim <- rxode2::rxSolve(mod, events = events) |>
as.data.frame() |>
dplyr::distinct(id, time, .keep_all = TRUE)
#> ℹ parameter labels from comments will be replaced by 'label()'
nrow(sim)
#> [1] 13400
mod_typical <- mod |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_typical <- rxode2::rxSolve(mod_typical, events = events) |>
as.data.frame() |>
dplyr::distinct(id, time, .keep_all = TRUE)
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalmat', 'etalfrac'
#> Warning: multi-subject simulation without without 'omega'Replicate Figure 2 (mean intracellular and plasma profiles)
# Replicates Figure 2 of Wang 2011: mean plasma and intracellular
# raltegravir concentration vs time after a single 400 mg dose.
sim_long <- sim |>
dplyr::filter(!is.na(Cc), time > 0) |>
dplyr::group_by(time) |>
dplyr::summarise(
plasma_median = median(Cc, na.rm = TRUE),
plasma_q05 = quantile(Cc, 0.05, na.rm = TRUE),
plasma_q95 = quantile(Cc, 0.95, na.rm = TRUE),
ic_median = median(Cic, na.rm = TRUE),
ic_q05 = quantile(Cic, 0.05, na.rm = TRUE),
ic_q95 = quantile(Cic, 0.95, na.rm = TRUE),
.groups = "drop"
)
# Reshape to long format for ggplot
sim_fig2 <- dplyr::bind_rows(
dplyr::transmute(sim_long, time, compartment = "Plasma",
median = plasma_median, q05 = plasma_q05, q95 = plasma_q95),
dplyr::transmute(sim_long, time, compartment = "Intracellular (PBMC)",
median = ic_median, q05 = ic_q05, q95 = ic_q95)
)
# Convert to nmol/L to match the paper's y-axis
sim_fig2 <- sim_fig2 |>
dplyr::mutate(
median_nM = median * 1e6 / mw_ral,
q05_nM = q05 * 1e6 / mw_ral,
q95_nM = q95 * 1e6 / mw_ral
)
ic50 <- 7 # nmol/L (top end of HIV-1 integrase IC50 range, Wang 2011 Fig 2 caption)
ggplot(sim_fig2, aes(time, median_nM, colour = compartment, fill = compartment)) +
geom_ribbon(aes(ymin = q05_nM, ymax = q95_nM), alpha = 0.15, colour = NA) +
geom_line() +
geom_hline(yintercept = ic50, linetype = "dashed", colour = "grey50") +
annotate("text", x = 40, y = ic50, label = "IC50 = 7 nM", vjust = -0.5, colour = "grey50") +
scale_y_log10() +
labs(x = "Time (h)", y = "Raltegravir concentration (nmol/L)",
colour = NULL, fill = NULL,
title = "Figure 2 -- Plasma and intracellular raltegravir after a single 400 mg dose",
caption = "Replicates Figure 2 of Wang 2011. Lines are simulated medians; ribbons are 5-95 percentile bands.")
Replicate Figure 4 (visual predictive check)
# Replicates Figure 4 of Wang 2011: VPC of plasma and intracellular RAL
# with observed concentrations overlaid against simulated percentiles.
# Wang 2011 reported 97% of observations within the 95% prediction
# interval. We reproduce the plasma and intracellular panels separately.
ggplot(sim_long, aes(time, plasma_median)) +
geom_ribbon(aes(ymin = plasma_q05, ymax = plasma_q95), alpha = 0.2) +
geom_line() +
scale_y_log10() +
labs(x = "Time (h)", y = "Plasma raltegravir (mg/L)",
title = "Figure 4A -- Plasma raltegravir VPC",
caption = "Replicates Figure 4A of Wang 2011 (median and 5-95 percentile band).")
ggplot(sim_long, aes(time, ic_median)) +
geom_ribbon(aes(ymin = ic_q05, ymax = ic_q95), alpha = 0.2) +
geom_line() +
scale_y_log10() +
labs(x = "Time (h)", y = "Intracellular raltegravir (mg/L)",
title = "Figure 4B -- Intracellular raltegravir VPC",
caption = "Replicates Figure 4B of Wang 2011 (median and 5-95 percentile band).")
PKNCA validation
We run PKNCA separately for plasma and intracellular concentrations, each with the cohort label as a single-level treatment grouping (the study had one treatment arm: 400 mg single dose).
# Plasma NCA
# rxSolve returns both Cc and Cic on every observation row; deduplicate to
# one row per (id, time) before passing to PKNCA.
sim_plasma <- sim |>
dplyr::filter(!is.na(Cc), time > 0) |>
dplyr::distinct(id, time, .keep_all = TRUE) |>
dplyr::transmute(id, time, Cc, treatment = "400 mg single oral dose")
dose_df <- tibble::tibble(
id = seq_len(n_sub),
time = 0,
amt = 400,
treatment = "400 mg single oral dose"
)
conc_obj <- PKNCA::PKNCAconc(sim_plasma, Cc ~ time | treatment + id,
concu = "mg/L", timeu = "h")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | treatment + id, doseu = "mg")
intervals <- data.frame(
start = 0, end = Inf,
cmax = TRUE, tmax = TRUE,
auclast = TRUE, aucinf.obs = TRUE, half.life = TRUE
)
nca_plasma <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals))
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#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
plasma_summary <- summary(nca_plasma)
knitr::kable(plasma_summary, caption = "Simulated plasma NCA (200-subject virtual cohort, 400 mg single dose).")| Interval Start | Interval End | treatment | N | AUClast (h*mg/L) | Cmax (mg/L) | Tmax (h) | Half-life (h) | AUCinf,obs (h*mg/L) |
|---|---|---|---|---|---|---|---|---|
| 0 | Inf | 400 mg single oral dose | 200 | NC | 1.14 [55.3] | 1.75 [0.500, 8.25] | 5.52 [2.81] | NC |
# Intracellular NCA (treating Cic as the observation)
sim_ic <- sim |>
dplyr::filter(!is.na(Cic), time > 0) |>
dplyr::distinct(id, time, .keep_all = TRUE) |>
dplyr::transmute(id, time, Cc = Cic, treatment = "400 mg single oral dose (intracellular)")
dose_df_ic <- dose_df |>
dplyr::mutate(treatment = "400 mg single oral dose (intracellular)")
conc_obj_ic <- PKNCA::PKNCAconc(sim_ic, Cc ~ time | treatment + id,
concu = "mg/L", timeu = "h")
dose_obj_ic <- PKNCA::PKNCAdose(dose_df_ic, amt ~ time | treatment + id, doseu = "mg")
nca_ic <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_ic, dose_obj_ic, intervals = intervals))
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
ic_summary <- summary(nca_ic)
knitr::kable(ic_summary, caption = "Simulated intracellular NCA (200-subject virtual cohort, 400 mg single dose).")| Interval Start | Interval End | treatment | N | AUClast (h*mg/L) | Cmax (mg/L) | Tmax (h) | Half-life (h) | AUCinf,obs (h*mg/L) |
|---|---|---|---|---|---|---|---|---|
| 0 | Inf | 400 mg single oral dose (intracellular) | 200 | NC | 0.125 [143] | 1.75 [0.500, 8.25] | 5.52 [2.81] | NC |
Comparison against published NCA
# Pull the simulated geometric mean (or median) values back as numeric
# from the typical-value (no-IIV, no-residual) simulation, and compare
# to the published geometric means converted from nmol/L to mg/L.
get_typ <- function(df, col) df[[col]][which.max(df[[col]])]
typ <- sim_typical |> dplyr::filter(!is.na(Cc))
typ_plasma_cmax <- max(typ$Cc, na.rm = TRUE)
typ_ic_cmax <- max(typ$Cic, na.rm = TRUE)
typ_plasma_c12 <- typ$Cc[abs(typ$time - 12) < 1e-6][1]
cmp <- tibble::tribble(
~metric, ~paper_mgL, ~typical_value_mgL,
"Plasma Cmax", nm_to_mgL(2246), typ_plasma_cmax,
"Plasma C12", nm_to_mgL(338.7), typ_plasma_c12,
"Intracellular Cmax", nm_to_mgL(383), typ_ic_cmax
)
cmp$ratio_typ_over_paper <- cmp$typical_value_mgL / cmp$paper_mgL
knitr::kable(cmp, digits = 4,
caption = "Wang 2011 geometric-mean NCA (converted to mg/L) vs. typical-value simulation from the packaged model. Differences arise because the typical value (no IIV) does not reproduce a small-N geometric mean exactly, and because the one-compartment fit gives an apparent half-life t1/2 = ln(2) * V/CL = 4.82 h compared to the 7.8 h NCA-derived half-life reported in the paper (see Assumptions and deviations).")| metric | paper_mgL | typical_value_mgL | ratio_typ_over_paper |
|---|---|---|---|
| Plasma Cmax | 0.9982 | 1.2016 | 1.2039 |
| Plasma C12 | 0.1505 | 0.2985 | 1.9829 |
| Intracellular Cmax | 0.1702 | 0.1346 | 0.7907 |
Assumptions and deviations
-
Number of transit compartments fixed at 2
(structural). Wang 2011 reports n = 2 as the optimal number of
transition compartments selected during model development, not as an
estimated theta with a precision estimate. The model encodes n = 2
implicitly in the ODE chain
(
depot -> transit1 -> transit2 -> central) and ties the transit-chain rate constant to MAT throughktr = (n + 1) / MAT = 3 / MAT. There is nofixed()ini entry because n is not a theta; it is a structural choice that determines the number ofd/dtlines. -
Mass-balance unit choice. The paper reports
concentrations in nmol/L; the packaged model carries concentrations in
mg/L (
units$concentration = "mg/L") and the dose is supplied asamt = 400withunits$dosing = "mg". The cross-checking conversion to nmol/L uses raltegravir MW = 444.42 g/mol. This matchesLee_2016_raltegravir’s unit convention. -
Exponential residual error interpretation. The
paper Methods state “Interindividual and residual unexplained
variability were estimated with an exponential error model” (Wang 2011
page 4091). In NONMEM this is Y = F * exp(eps) with eps ~ N(0, sigma^2).
nlmixr2’s
~ lnorm(expSd)is the exact analogue withexpSd = sigmaon the log scale. Wang 2011 Table 1 reports residual error as a percentage in the same column it reports IIV %CV; following the standard NONMEM$SIGMA-on-log-scale reporting convention, the percentage is read assigma * 100%(expSd = 0.867for plasma;expSd_Cic = 0.649for intracellular). For IIV the percentages are read as linear-space %CV and converted viaomega^2 = log(1 + CV^2), which is the standard nlmixr2lib convention matchingLee_2016_raltegravir. -
Apparent vs. NCA half-life mismatch. The
one-compartment fit gives an apparent terminal half-life
t1/2 = ln(2) * V / CL = 0.693 * 272 / 39.1 ~= 4.82 h, whereas the paper’s NCA reportst1/2 = 7.8 h(95% CI 5.5-11.3 h) using terminal-phase regression over 24 and 48 h time points. The paper Discussion acknowledges this: “our attempts to fit the data to a two-compartment model were not successful, most likely due to little data collected during the beta-elimination phase”. The simulated trajectories therefore decline somewhat faster than the late-time observed data; this is a feature of the published 1-compartment model, not a transcription error. Larger studies cited by the authors (Dickinson et al., Iwamoto et al.) reported either two-compartment fits or different one-compartment parameter estimates – consult those papers for a model intended for late-time extrapolation. -
Accumulation ratio is a misnomer for raltegravir.
Wang 2011 names the parameter ACR (accumulation ratio) but the point
estimate of 11.2% means raltegravir does NOT accumulate intracellularly.
The packaged model maps this parameter onto the canonical paper-named
bare parameter
frac(a unitless fraction in (0, 1)); the label and inline comments preserve the paper’s “accumulation ratio” name and emphasise the (0, 1) interpretation. The paper itself states “this result is consistent with simple diffusion of unbound RAL into cells” (Discussion, page 4094). -
Intracellular model has no separate compartment
kinetics. Wang 2011 Eq.:
C_IC,obs = ACR * C_plasma,pred * exp(eps_IC)– the intracellular concentration is an empirical multiplicative transform of the predicted plasma concentration, not a separate compartment with its own ODE. The packaged model implements this exactly asCic <- frac * Ccfollowed byCic ~ lnorm(expSd_Cic). There is no intracellular ODE state, and PBMC isolation / processing effects (which the paper Discussion notes contribute to the high intracellular residual error of 64.9%) enter only throughexpSd_Cic. - Sample size is small. Six subjects produce wide confidence intervals on every parameter (RSE 15-56%). The visual predictive check in Wang 2011 Fig. 4 covered 97% of observed concentrations, but the authors explicitly cautioned (Discussion, page 4094) that “large pharmacokinetic studies are required to further characterize the pharmacokinetics of RAL before the population pharmacokinetic model could be applied in a clinical setting.” Treat the simulated NCA values as illustrative rather than predictive for new dosing scenarios.