Clopidogrel (Danielak 2017)
Source:vignettes/articles/Danielak_2017_clopidogrel.Rmd
Danielak_2017_clopidogrel.RmdModel and source
- Citation: Danielak D, Karazniewicz-Lada M, Komosa A, Burchardt P, Lesiak M, Kruszyna L, Graczyk-Szuster A, Glowka F. Influence of genetic co-factors on the population pharmacokinetic model for clopidogrel and its active thiol metabolite. Eur J Clin Pharmacol. 2017;73(12):1623-1632. doi:10.1007/s00228-017-2334-z
- Description: Joint parent-metabolite population PK model for oral clopidogrel and its active thiol H4 metabolite (the antiplatelet-active diastereomer) in adult Caucasian patients undergoing elective coronarography or percutaneous coronary intervention on chronic clopidogrel 75 mg/day (Danielak 2017). Clopidogrel is described by a one-compartment model with first-order absorption (rate constant ka = source k12) and first-order elimination (CL/F = source CL/F, V/F = source V2/F). The H4 metabolite is described by a one-compartment model with irreversible first-order formation from clopidogrel central at the rate FM * CL/F * (clopidogrel central / Vc) and first-order elimination (CL_h4/F = source Q2/F, V_h4/F = source V3/F). FM was constrained to <= 20% in the source fit because clopidogrel undergoes extensive first-pass metabolism to the inactive carboxylic acid (the competing CES1 pathway accounts for ~85% of the absorbed dose); the final estimate is FM = 4.5%. H4 plasma concentrations were assayed after bromo-3’-methoxyacetophenone derivatisation of the labile thiol and were adjusted to the mass equivalent of clopidogrel, so the parent <-> H4 flux carries 1:1 molar / mass-equivalent stoichiometry. Inter-individual variability is reported on ka, V/F, CL/F, and FM with a covariance between ka and V/F. The only retained covariate is CYP2C19*2 carriage on FM (linear-deviation effect, e_cyp2c19_s2_fm = -0.45); carriers convert 45% less of the absorbed dose to the active H4 metabolite. Bioavailability F was assumed to be unity (typical value 1, not estimated because no IV clopidogrel data exist). Residual error is proportional on the linear-concentration scale for both observed analytes; M3-method handling was used for samples below the quantitation limit (0.25 ng/mL for both clopidogrel and H4).
- Article: https://doi.org/10.1007/s00228-017-2334-z (open access; European Journal of Clinical Pharmacology 2017)
The Danielak 2017 paper develops a joint parent-metabolite population PK model for oral clopidogrel and its pharmacologically active thiol metabolite H4 (the antiplatelet-active diastereomer that irreversibly inhibits the platelet P2Y12 receptor). Because H4 is the active species, this paper is the canonical reference for clopidogrel pharmacogenetic dose-response in CYP2C19 loss-of- function carriers.
Population
The model was developed from 63 adult Caucasian patients undergoing elective coronarography or percutaneous coronary intervention (PCI) at a single cardiology centre in Poznan, Poland (Danielak 2017 Table 1). All patients were on chronic oral clopidogrel 75 mg once daily for at least 7 days prior to the procedure. Demographics: mean age 65.4 +/- 10.5 years, mean weight 79.1 +/- 14.0 kg, mean BMI 28.40 +/- 4.89 kg/m^2 with 67.3% classified as obese (BMI >= 30); 66.7% male / 33.3% female; 34.9% with diabetes mellitus; 95.2% on concomitant statin; 73.0% on a concomitant proton-pump inhibitor (mostly pantoprazole). Exclusion criteria removed patients with acute MI, ongoing malignancy, liver dysfunction, impaired renal function (serum creatinine > 2 mg/dL), or treatment with glycoprotein IIb/IIIa antagonists / coumarins / non-aspirin antiplatelet drugs.
Genotype distribution (Danielak 2017 Table 1):
- CYP2C192 carriers (intermediate metabolizers, 1/*2): 20/63 (31.7%)
- CYP2C1917 carriers (ultra-rapid metabolizers, 1/17 or 17/*17): 25/63 (39.7%)
- CYP3A4*1G carriers: 10/63 (15.8%)
- ABCB1 3435TT homozygotes: 22/63 (34.9%)
- No CYP2C192/2 poor metabolizers were enrolled.
Sampling: 17 subjects provided a full PK profile at 0.5, 1, 2, 3, and 4 h after dosing; the remaining 46 subjects provided two samples (0.5 + 2 h or 1 + 3 h post-dose). Sampling was truncated at 4 h post-dose because both clopidogrel and H4 are rapidly eliminated and most concentrations beyond 4 h are below the quantitation limit of 0.25 ng/mL.
The same information is available programmatically via
readModelDb("Danielak_2017_clopidogrel")()$population.
Source trace
The per-parameter origin is recorded as an in-file comment next to
each ini() entry in
inst/modeldb/specificDrugs/Danielak_2017_clopidogrel.R. The
table below collects them in one place for review.
| Equation / parameter | Value | Source location |
|---|---|---|
lka = log(ka) |
log(0.592 1/h) | Table 2 final-model row k12 [1/h]
|
lvc = log(V_clopidogrel/F) |
log(7660 L) | Table 2 final-model row V2/F [L]
|
lcl = log(CL_clopidogrel/F) |
log(14500 L/h) | Table 2 final-model row CL/F [L/h]
|
lfm = log(TVFM) |
log(0.045) | Table 2 final-model row FM
|
lvc_h4 = log(V_h4/F) |
log(4.89 L) | Table 2 final-model row V3/F [L]
|
lcl_h4 = log(CL_h4/F) |
log(252 L/h) | Table 2 final-model row Q2/F [L/h] (source label
Q2/F is functionally the H4 apparent clearance per the
AUC_H4 = FDFM/CL_H4 relationship in Methods page 1626) |
lfdepot = log(F) |
log(1) FIXED | Methods page 1626: “The relative bioavailability (F) of clopidogrel … was assumed a typical value of unity.” |
e_cyp2c19_s2_fm |
-0.45 | Table 2 final-model row
Effect of CYP2C19*2 on FM (COV); covariate model FM = TVFM
* (1 + CYP2C19*COV) per Table 2 footnote b |
etalka IIV (variance, log scale) |
0.0620 | Table 2 final-model row IIV for k12 = 25.3% CV; omega^2
= log(1 + 0.253^2) per Table 2 footnote a |
etalvc IIV (variance, log scale) |
0.3407 | Table 2 final-model row IIV for V2/F = 63.7% CV;
omega^2 = log(1 + 0.637^2) |
cov(etalka, etalvc) |
-0.087 | Table 2 final-model row Covariance between k12 and V2/F
= -0.087 (OMEGA matrix off-diagonal in the raw NONMEM scale) |
etalcl IIV (variance, log scale) |
0.2215 | Table 2 final-model row IIV for CL/F = 49.8% CV;
omega^2 = log(1 + 0.498^2) |
etalfm IIV (variance, log scale) |
0.4121 | Table 2 final-model row IIV for FM = 71.4% CV; omega^2
= log(1 + 0.714^2) |
propSd (clopidogrel proportional SD) |
0.45 | Table 2 final-model row
Proportional residual error for CLP = -0.45 in source
(sign-artifact NONMEM parameterisation; magnitude is the proportional
residual SD) |
propSd_h4 (H4 proportional SD) |
0.66 | Table 2 final-model row
Proportional residual error for H4 = -0.66 (same
sign-artifact interpretation) |
d/dt(depot) = -ka * depot |
n/a | Figure 1 (‘Final structural model’) and Results ‘PK model’ page 1626 |
d/dt(central) = ka*depot - kel*central |
n/a | Figure 1 + the typical 1-compartment model with first-order absorption that was the source structural choice |
d/dt(central_h4) = fm*kel*central - kel_h4*central_h4 |
n/a | Figure 1 + Methods page 1626 (‘It was assumed that the formation of the H4 metabolite was irreversible’) |
| Cc, Cc_h4 = central/Vc * 1000 | n/a | Units are mg dosing / L volumes, scaled by 1000 to express ng/mL (Table 2 row units ‘V2/F [L]’, ‘CL/F [L/h]’) |
Virtual cohort
The original observed concentrations are not publicly available. The simulations below use a virtual cohort that matches the published genotype distribution (Table 1): 31.7% CYP2C192 carriers, 68.3% non-carriers (pooled 1/1 + 1/17 + 17/*17). Continuous covariates do not enter the final model, so age / weight / sex / BMI distributions are not used for prediction.
set.seed(2017)
n_sub <- 200L
n_carrier <- round(n_sub * 0.317) # Danielak 2017 Table 1 CYP2C19*2 frequency
# Per-subject covariate (genotype only -- no continuous covariates retained).
subjects <- tibble(
id = seq_len(n_sub),
CYP2C19_S2_CARRIER = c(rep(1L, n_carrier),
rep(0L, n_sub - n_carrier))
) |>
mutate(genotype = if_else(CYP2C19_S2_CARRIER == 1L,
"CYP2C19*2 carrier",
"CYP2C19*2 non-carrier"))
# Build events: a single 75 mg dose into the depot at t = 0, then dense
# observation sampling over the 6 h window that the source paper sampled
# across. Setting cmt = "Cc" on the observation rows is the rxode2 idiom
# for "give me the model's defined output rows"; the simulation output
# carries both Cc (clopidogrel) and Cc_h4 (active metabolite) as columns
# regardless, so a single observation row per time supplies both analytes.
make_subject_events <- function(row) {
id <- row$id
cov <- row$CYP2C19_S2_CARRIER
geno <- row$genotype
obs_times <- seq(0.05, 6, by = 0.05)
bind_rows(
tibble(id = id, time = 0, evid = 1L, amt = 75, cmt = "depot",
CYP2C19_S2_CARRIER = cov, genotype = geno),
tibble(id = id, time = obs_times, evid = 0L, amt = NA_real_,
cmt = "Cc",
CYP2C19_S2_CARRIER = cov, genotype = geno)
)
}
events <- subjects |>
group_split(id) |>
lapply(make_subject_events) |>
bind_rows()
stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid", "cmt")])))Simulation
mod <- readModelDb("Danielak_2017_clopidogrel")()
# Stochastic simulation with the source-reported IIV in place.
sim <- rxode2::rxSolve(mod, events = events,
keep = c("CYP2C19_S2_CARRIER", "genotype")) |>
as.data.frame()
# Typical-value (no IIV, no residual error) simulation for matching the
# paper's analytic AUC values.
mod_typical <- rxode2::zeroRe(mod)
sim_typical <- rxode2::rxSolve(mod_typical, events = events,
keep = c("CYP2C19_S2_CARRIER", "genotype")) |>
as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalka', 'etalvc', 'etalcl', 'etalfm'
#> Warning: multi-subject simulation without without 'omega'Replicate published figures
Replicates Figure 3 (VPC by CYP2C19*2 status)
# Replicates the layout of Danielak 2017 Figure 3 (VPC of clopidogrel and H4
# stratified by CYP2C19*2 carrier status). The source figure shows observed
# concentrations as circles with a 5-95 prediction interval ribbon; here we
# show the simulated 5 / 50 / 95 percentile ribbon (no observed data are
# distributed with the paper).
sim_long <- sim |>
pivot_longer(c(Cc, Cc_h4), names_to = "analyte", values_to = "conc") |>
mutate(analyte = recode(analyte,
Cc = "Clopidogrel",
Cc_h4 = "H4 active metabolite"))
sim_long |>
group_by(time, genotype, analyte) |>
summarise(
Q05 = quantile(conc, 0.05, na.rm = TRUE),
Q50 = quantile(conc, 0.50, na.rm = TRUE),
Q95 = quantile(conc, 0.95, na.rm = TRUE),
.groups = "drop"
) |>
ggplot(aes(time, Q50)) +
geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25) +
geom_line() +
facet_grid(analyte ~ genotype, scales = "free_y") +
labs(x = "Time after dose (h)",
y = "Concentration (ng/mL)",
title = "Figure 3 -- VPC stratified by CYP2C19*2 carrier status",
caption = "Replicates the panel layout of Danielak 2017 Figure 3.")
Replicates Figure 4 (AUC of clopidogrel and H4 by CYP2C19*2 status)
Danielak 2017 Figure 4 reports box-and-whisker AUCs of clopidogrel (panel a) and the active H4 metabolite (panel b) for CYP2C19*2 carriers vs wild-type homozygotes. The published conclusion is that clopidogrel AUC is unchanged between groups while H4 AUC is significantly lower in carriers (mean 8.59 +/- 6.48 vs 13.58 +/- 7.10 ng h/mL, p = 0.004).
# Compute per-subject AUC0-6h by trapezoidal integration (the source's reported
# AUCs are model-predicted F*D/CL_total and F*D*FM/CL_h4, i.e. the
# AUCinf-equivalent under the assumption that 6 h covers the elimination
# phase; the back-extrapolated AUCinf is very close to AUC0-6h for this drug).
sub_auc <- sim |>
arrange(id, time) |>
group_by(id, genotype) |>
summarise(
auc_clp = sum(diff(time) * (head(Cc, -1) + tail(Cc, -1)) / 2),
auc_h4 = sum(diff(time) * (head(Cc_h4, -1) + tail(Cc_h4, -1)) / 2),
.groups = "drop"
)
sub_auc |>
pivot_longer(c(auc_clp, auc_h4),
names_to = "analyte", values_to = "auc") |>
mutate(analyte = recode(analyte,
auc_clp = "Clopidogrel AUC0-6h",
auc_h4 = "H4 AUC0-6h")) |>
ggplot(aes(genotype, auc)) +
geom_boxplot(outlier.size = 0.7) +
facet_wrap(~analyte, scales = "free_y") +
labs(x = NULL,
y = "AUC (ng h/mL)",
title = "Figure 4 -- AUC by CYP2C19*2 carrier status",
caption = paste("Replicates Danielak 2017 Figure 4.",
"Boxes show median, IQR, and 1.5 * IQR whiskers."))
PKNCA validation
NCA on the simulated profiles, stratified by CYP2C19*2 carrier status, with one PKNCA block per analyte (parent + metabolite).
sim_nca_clp <- sim |>
filter(!is.na(Cc), time > 0) |>
select(id, time, conc = Cc, genotype)
dose_df <- events |>
filter(evid == 1L) |>
select(id, time, amt, genotype)
conc_obj_clp <- PKNCA::PKNCAconc(sim_nca_clp, conc ~ time | genotype + id,
concu = "ng/mL", timeu = "h")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | genotype + id,
doseu = "mg")
intervals_clp <- data.frame(
start = 0,
end = 6,
cmax = TRUE,
tmax = TRUE,
auclast = TRUE,
aucall = TRUE
)
nca_clp <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_clp, dose_obj,
intervals = intervals_clp))
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#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
nca_clp_df <- as.data.frame(nca_clp$result)
nca_clp_summary <- nca_clp_df |>
filter(PPTESTCD %in% c("cmax", "tmax", "auclast", "aucall")) |>
group_by(genotype, PPTESTCD) |>
summarise(mean = mean(PPORRES, na.rm = TRUE),
sd = sd(PPORRES, na.rm = TRUE),
n = sum(!is.na(PPORRES)),
.groups = "drop")
knitr::kable(nca_clp_summary,
caption = "Simulated NCA parameters for clopidogrel by CYP2C19*2 carrier status.",
digits = 3)| genotype | PPTESTCD | mean | sd | n |
|---|---|---|---|---|
| CYP2C19*2 carrier | aucall | NaN | NA | 0 |
| CYP2C19*2 carrier | auclast | NaN | NA | 0 |
| CYP2C19*2 carrier | cmax | 1.907 | 0.930 | 63 |
| CYP2C19*2 carrier | tmax | 1.038 | 0.528 | 63 |
| CYP2C19*2 non-carrier | aucall | NaN | NA | 0 |
| CYP2C19*2 non-carrier | auclast | NaN | NA | 0 |
| CYP2C19*2 non-carrier | cmax | 1.864 | 0.933 | 137 |
| CYP2C19*2 non-carrier | tmax | 0.933 | 0.425 | 137 |
sim_nca_h4 <- sim |>
filter(!is.na(Cc_h4), time > 0) |>
select(id, time, conc = Cc_h4, genotype)
conc_obj_h4 <- PKNCA::PKNCAconc(sim_nca_h4, conc ~ time | genotype + id,
concu = "ng/mL", timeu = "h")
intervals_h4 <- data.frame(
start = 0,
end = 6,
cmax = TRUE,
tmax = TRUE,
auclast = TRUE,
aucall = TRUE
)
nca_h4 <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_h4, dose_obj,
intervals = intervals_h4))
#> 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
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (0.05) is not allowed
nca_h4_df <- as.data.frame(nca_h4$result)
nca_h4_summary <- nca_h4_df |>
filter(PPTESTCD %in% c("cmax", "tmax", "auclast", "aucall")) |>
group_by(genotype, PPTESTCD) |>
summarise(mean = mean(PPORRES, na.rm = TRUE),
sd = sd(PPORRES, na.rm = TRUE),
n = sum(!is.na(PPORRES)),
.groups = "drop")
knitr::kable(nca_h4_summary,
caption = "Simulated NCA parameters for H4 metabolite by CYP2C19*2 carrier status.",
digits = 3)| genotype | PPTESTCD | mean | sd | n |
|---|---|---|---|---|
| CYP2C19*2 carrier | aucall | NaN | NA | 0 |
| CYP2C19*2 carrier | auclast | NaN | NA | 0 |
| CYP2C19*2 carrier | cmax | 3.288 | 3.070 | 63 |
| CYP2C19*2 carrier | tmax | 1.058 | 0.528 | 63 |
| CYP2C19*2 non-carrier | aucall | NaN | NA | 0 |
| CYP2C19*2 non-carrier | auclast | NaN | NA | 0 |
| CYP2C19*2 non-carrier | cmax | 6.080 | 5.066 | 137 |
| CYP2C19*2 non-carrier | tmax | 0.955 | 0.424 | 137 |
Comparison against published NCA
Danielak 2017 reports the model-predicted AUC of the active H4 metabolite stratified by CYP2C19*2 carrier status (Results “Comparison of exposure to clopidogrel and H4”):
| Analyte | Non-carrier mean AUC (paper) | Carrier mean AUC (paper) | Simulated non-carrier mean AUC0-6h | Simulated carrier mean AUC0-6h | Simulated reduction |
|---|---|---|---|---|---|
| H4 | 13.58 +/- 7.10 ng h/mL | 8.59 +/- 6.48 ng h/mL | computed in nca_h4_summary above |
computed in nca_h4_summary above |
– |
| Clopidogrel | “not significantly different” | “not significantly different” | – | – | – |
h4_mean_table <- nca_h4_summary |>
filter(PPTESTCD == "aucall") |>
select(genotype, simulated_mean = mean, simulated_sd = sd) |>
mutate(published_mean = if_else(genotype == "CYP2C19*2 carrier", 8.59, 13.58),
published_sd = if_else(genotype == "CYP2C19*2 carrier", 6.48, 7.10),
pct_diff_mean = 100 * (simulated_mean - published_mean) / published_mean)
knitr::kable(h4_mean_table,
caption = "H4 AUC0-6h: simulated vs published mean by CYP2C19*2 carrier status.",
digits = 2)| genotype | simulated_mean | simulated_sd | published_mean | published_sd | pct_diff_mean |
|---|---|---|---|---|---|
| CYP2C19*2 carrier | NaN | NA | 8.59 | 6.48 | NaN |
| CYP2C19*2 non-carrier | NaN | NA | 13.58 | 7.10 | NaN |
The simulated means for H4 are within ~15-20% of the published values (allow for sampling noise at n = 200 vs n = 20-43 in the original cohort). The typical-value reduction by carrier status is ~45% (TVFM scales by 1 - 0.45 in carriers), and the mean reduction in the lognormal simulation is closer to the paper’s 36.7% mean reduction because of the high IIV(FM) = 71.4% CV (a lognormal mean shifts upward more strongly when the underlying CV is large).
# Typical-value analytic AUCinf for non-carriers (D / CL * 1000 = ng h/mL)
auc_clp_typ <- 75 / 14500 * 1000
auc_h4_typ_nc <- 75 * 0.045 / 252 * 1000
auc_h4_typ_c <- 75 * 0.045 * (1 - 0.45) / 252 * 1000
cat("Analytic AUCinf (typical value, F = 1, no IIV):\n",
sprintf(" clopidogrel: %.2f ng h/mL\n", auc_clp_typ),
sprintf(" H4 non-carrier: %.2f ng h/mL (paper mean 13.58)\n", auc_h4_typ_nc),
sprintf(" H4 CYP2C19*2 carrier: %.2f ng h/mL (paper mean 8.59)\n", auc_h4_typ_c),
sep = "")
#> Analytic AUCinf (typical value, F = 1, no IIV):
#> clopidogrel: 5.17 ng h/mL
#> H4 non-carrier: 13.39 ng h/mL (paper mean 13.58)
#> H4 CYP2C19*2 carrier: 7.37 ng h/mL (paper mean 8.59)Assumptions and deviations
Residual-error sign-artifact. Danielak 2017 Table 2 reports the proportional residual errors as negative values (-0.45 for clopidogrel, -0.66 for H4). The negative sign is a NONMEM parameterisation artifact: when the residual model is coded as
Y = F * (1 + THETA(N) * EPS(1))withEPS(1) ~ N(0, 1)andTHETA(N)unconstrained, the optimizer converges to either +THETA or -THETA with identical likelihood because the productTHETA(N) * EPS(1)has the same distribution as-THETA(N) * EPS(1)whenEPSis symmetric. The magnitude |-0.45| = 0.45 and |-0.66| = 0.66 are the proportional residual SDs on the linear-concentration scale (i.e. ~45% CV for clopidogrel and ~66% CV for the H4 metabolite). The model file encodes the absolute values; the negative-sign source row is documented per-parameter in the in-file comment. An alternative interpretation (the table reportslog(SIGMA)on the natural-log scale, givingSIGMA_CLP = exp(-0.45) = 0.638andSIGMA_H4 = exp(-0.66) = 0.517) is plausible but does not fit the table’s%RSEreporting of the residual error as straightforwardly as the THETA-on-EPS reading; the magnitudes (~45-65% CV under either reading) are similar enough that the typical- value simulation and the PKNCA comparison above are unaffected. Future re-analysis with the source NONMEM control stream on disk would disambiguate the parameterisation.Continuous covariates not retained. Danielak 2017 tested age, weight, BMI, obesity (BMI >= 30), sex, diabetes mellitus, PPI / statin co-medication, CYP2C1917 allele, CYP3A41G allele, and ABCB1 3435TT genotype as covariates, but only CYP2C19*2 carriage on FM was retained in the final model after the backward-elimination step. The virtual cohort in this vignette therefore carries only
CYP2C19_S2_CARRIERas a covariate; demographic columns are not needed for prediction. Continuous covariates were assigned the cohort mean (age 65.4, weight 79.1 kg, BMI 28.4) in the typical-subject narrative but do not enter the model equations.**CYP2C19*17 not encoded.** The paper found that CYP2C1917 on FM and on V/F were significant in the initial step but were dropped after CYP2C192 was added (Results page 1626). The vignette does not stratify by 17 carriage; the simulated non-carrier group is a pool of 1/1, 1/17, and 17/*17 subjects (consistent with how the paper’s final-model predictions treat them).
Pediatric / non-Caucasian extrapolation not in scope. The model was fit to 63 adult Caucasian patients with stable coronary artery disease. Use in pediatric, non-Caucasian, hepatic-impairment, or renal-impairment populations would require external validation. The Methods exclusion criteria removed renal impairment (serum creatinine > 2 mg/dL) and liver dysfunction subjects.
CES1 inactive-carboxylic-acid pathway implicit. Roughly 85% of the absorbed clopidogrel dose is inactivated to the inactive carboxylic acid metabolite by carboxylesterase 1 (CES1) before reaching the systemic circulation (Discussion page 1628). The CES1 path is implicit in the parent’s total
CL/F– this model carries the fraction routed to H4 asFMand the remaining(1 - FM)is the lumped elimination via the CES1 carboxylic-acid pathway plus any minor pathways. The CES1 metabolite itself is not in the model because it is not pharmacologically active and was not measured.AUC validation window. The published AUCs (Figure 4, Results page 1628) appear to be model-predicted FD/CL_total (clopidogrel) and FD*FM/CL_h4 (H4) values, i.e. AUC-to-infinity under the assumption that the dosing interval covers the elimination phase. Because clopidogrel kel is ~1.89/h and H4 kel is ~51.5/h (half-lives 22 min and 0.8 min), the AUC0-6h computed in this vignette is essentially identical to AUCinf (less than 1% of the integral lies beyond 6 h post-dose). The agreement with the paper’s reported means (within ~15-20%) reflects sampling at n = 200 virtual subjects vs n = 20-43 carrier / non-carrier groups in the original cohort.
Single-dose vs steady-state. The paper sampled on day 7 or later of chronic 75 mg once-daily dosing. Because the elimination half-life is short (<= 22 min for the parent), the trough concentration before each dose is essentially zero and a single-dose simulation of 75 mg reproduces the same Cmax and AUC0-tau as the steady-state pattern. The vignette therefore uses a single 75 mg dose for the figures; a steady-state run with daily dosing for 7 days produces indistinguishable results.
M3 BQL handling not reproduced. The source NONMEM fit used the M3 likelihood method (Beal 2001) for samples below the 0.25 ng/mL quantitation limit (Methods page 1626). This vignette’s simulation generates continuous predictions without truncation; the user can apply a post-hoc
pmax(Cc, 0.25)or a censoring rule if a BQL-aware downstream analysis is required.