Savic_2017_cladribine
Source:vignettes/articles/Savic_2017_cladribine.Rmd
Savic_2017_cladribine.RmdModel and source
- Citation: Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson MO. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis. Clin Pharmacokinet. 2017 Oct;56(10):1245-1253. doi:10.1007/s40262-017-0516-6. PMID: 28255848; PMCID: PMC5591346.
- Description: Population PK model for cladribine (CdA) in patients with relapsing-remitting multiple sclerosis (Savic 2017): three-compartment disposition with first-order oral absorption, separate fasted vs fed (or unknown food-state) absorption parameters, renal clearance proportional to Cockcroft-Gault creatinine clearance, and a multiplicative non-renal-clearance effect of concomitant subcutaneous interferon beta-1a coadministration.
- Article: https://doi.org/10.1007/s40262-017-0516-6
Population
The Savic 2017 dataset pools four clinical studies in patients with relapsing-remitting multiple sclerosis (Table 2 of the source paper):
- Study 25803 (phase I, n = 16): randomized two-period crossover; 3 mg IV infusion over 1 h or 10 mg single oral tablet, with parent cladribine (CdA) and metabolite 2-chloroadenine (CAde) plasma and urine sampling.
- Study 26127 (phase I, n = 16): food-effect crossover, single 10 mg oral tablet in fed vs fasted sequence.
- Study 26486 (phase I, n = 16): cladribine-and-interferon-beta-1a drug-drug interaction study; oral cladribine 10 mg daily for 5 consecutive days with subcutaneous IFN beta-1a 8.8/22/44 ug three times weekly.
- Study 25643 (CLARITY phase III, n = 125; NCT00213135): 96-week, double-blind, placebo-controlled trial of cumulative 3.5 or 5.25 mg/kg oral cladribine tablets over 2 years.
Pooled demographics (source paper Table 3): N = 173, age range 19-65 years (median 40), body weight 48.5-116.1 kg (median 69.2), 65.9 % female, Cockcroft-Gault creatinine clearance 49.6-244.4 mL/min (median 107.9). The original dataset contained 4790 concentration-time records; 45 % were excluded (96.5 % of those for BLQ), leaving 2619 plasma and urine records for the population analysis.
str(rxode2::rxode(readModelDb("Savic_2017_cladribine"))$population)
#> ℹ parameter labels from comments will be replaced by 'label()'
#> List of 15
#> $ species : chr "human"
#> $ n_subjects : int 173
#> $ n_studies : int 4
#> $ age_range : chr "19-65 years"
#> $ age_median : chr "40 years"
#> $ weight_range : chr "48.5-116.1 kg"
#> $ weight_median : chr "69.2 kg"
#> $ sex_female_pct: num 65.9
#> $ race_ethnicity: chr "Not reported in detail; multinational phase I and phase III studies in patients with relapsing-remitting multiple sclerosis"
#> $ disease_state : chr "Relapsing-remitting multiple sclerosis"
#> $ dose_range : chr "Phase I: 3 mg IV infusion over 1 h, 10 mg single oral tablet, or 1.75 mg/kg orally over 8 weeks +/- subcutaneou"| __truncated__
#> $ regions : chr "Multinational (CLARITY phase III; NCT00213135)"
#> $ renal_function: chr "CLCR median 107.9 mL/min, range 49.6-244.4 mL/min (Cockcroft-Gault, raw)"
#> $ co_medication : chr "Phase I drug-drug interaction study (26486) coadministered subcutaneous IFN beta-1a (Rebif); 16 of 173 patients"| __truncated__
#> $ notes : chr "Pooled analysis of four clinical studies: 25803 (phase I IV+oral crossover, n=16), 26127 (phase I food-effect c"| __truncated__Source trace
Per-parameter origin is recorded inline next to each
ini() entry in
inst/modeldb/specificDrugs/Savic_2017_cladribine.R.
Consolidated here for review:
| Equation / parameter | Value | Source location |
|---|---|---|
lka (Ka, fasted) |
1.08 h^-1 | Table 4 (RSE 21.14 %) |
e_fed_ka (FED on log-Ka) |
log(1.03 / 1.08) = -0.0474 | Table 4 (“unknown/fed” Ka = 1.03 h^-1) |
logitf (logit of F, fasted) |
logit(0.456) = -0.1765 | Table 4 (RSE 7.03 %); footnote d “Variance on a logit scale” |
e_fed_logitf (FED on logit-F) |
logit(0.4) - logit(0.456) = -0.229 | Table 4 (“unknown/fed” F = 0.4) |
lmtt_fed (lag time approximation, fed) |
log(0.910 h) = -0.0943 | Table 4 mean transit time (fed state) = 0.910 h |
lcl_renal_typ (CLR at typical CRCL) |
log(22.2) = 3.100 | Table 4 CLR coefficient 3.52 dimensionless; CLR = 22.2 L/h at CLCR = 6.31 L/h = 105.2 mL/min |
lcl_nonrenal (CLNR, monotherapy) |
log(23.4) = 3.153 | Table 4 (RSE 9.58 %) |
e_ifn_clnr (IFN beta-1a fractional CLNR increase) |
0.21 | Table 4 (“Fold increase in CLNR in the presence of IFN beta-1a” = 1.21) |
lvc (V1) |
log(44.0) = 3.784 | Table 4 (RSE 22.77 %) |
lq (Q3) |
log(14.3) = 2.660 | Table 4 (RSE 7.73 %) |
lq2 (Q4) |
log(53.7) = 3.983 | Table 4 (RSE 19.06 %) |
lvp (V3) |
log(347) = 5.849 | Table 4 (RSE 6.07 %) |
lvp2 (V4) |
log(89.5) = 4.494 | Table 4 (RSE 7.97 %) |
etalka (BSV Ka, variance) |
0.102 | Table 4 (RSE 62.53 %) |
etalogitf (BSV F, logit-scale variance) |
0.223 | Table 4 (RSE 19.13 %, footnote d) |
etalcl_nonrenal (BSV CLNR, variance) |
0.00574 | Table 4 (RSE 64.41 %) |
etalvc (BSV V1, variance) |
0.209 | Table 4 (RSE 72.51 %) |
etalq (BSV Q3/Q4/V3/V4 shared, variance) |
0.0365 | Table 4 (RSE 28.47 %, single shared eta) |
propSd (proportional residual, plasma) |
0.353 | Table 4 RUV plasma (oral, study 25643) = 35.3 % |
| Three-compartment ODE structure | n/a | Methods 2.3.1 (“Model I A three-compartment model best described the PK of CdA”) and Figure 1 |
| CLR = coefficient * CRCL | n/a | Methods 3.2.1 and Table 4 footnotes b, c |
| IFN beta-1a effect on CLNR | multiplicative *1.21 | Methods 3.2.1 (Model IV) |
Virtual cohort
Original observed data are not publicly available. The figures below use a virtual population whose covariate distributions approximate the published pooled demographics (Table 3).
set.seed(7032017)
n_sub <- 100L
make_cohort <- function(n, label, fed, ifnb1a, crcl_mean = 107.9,
crcl_sd = 35, id_offset = 0L) {
ids <- id_offset + seq_len(n)
base <- tibble::tibble(
id = ids,
cohort = label,
CRCL = pmax(40, rnorm(n, mean = crcl_mean, sd = crcl_sd)),
FED = as.integer(fed),
CONMED_IFNB1A = as.integer(ifnb1a)
)
obs_grid <- c(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72)
expand_one <- function(row) {
dose <- data.frame(id = row$id, cohort = row$cohort, time = 0,
evid = 1L, amt = 10, cmt = "depot",
CRCL = row$CRCL, FED = row$FED,
CONMED_IFNB1A = row$CONMED_IFNB1A)
obs <- data.frame(id = row$id, cohort = row$cohort, time = obs_grid,
evid = 0L, amt = 0, cmt = "Cc",
CRCL = row$CRCL, FED = row$FED,
CONMED_IFNB1A = row$CONMED_IFNB1A)
rbind(dose, obs)
}
rows <- split(base, base$id)
do.call(rbind, lapply(rows, expand_one))
}
events <- dplyr::bind_rows(
make_cohort(n_sub, "10 mg oral, fasted, no IFN", fed = 0, ifnb1a = 0,
id_offset = 0L),
make_cohort(n_sub, "10 mg oral, fed, no IFN", fed = 1, ifnb1a = 0,
id_offset = 1*n_sub),
make_cohort(n_sub, "10 mg oral, fasted, + IFN beta-1a", fed = 0, ifnb1a = 1,
id_offset = 2*n_sub)
)
stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid")])))Simulation
mod <- readModelDb("Savic_2017_cladribine")
sim <- rxode2::rxSolve(mod(), events = events, keep = c("cohort"))
sim <- as.data.frame(sim)Replicate published figures
Figure 2 / Figure 4 – typical-value plasma concentration profile
Savic 2017 Figure 2c shows the VPC for a single oral 10 mg dose in fasted state. We reproduce the typical-value (median) cladribine plasma concentration over 72 hours.
typical_summary <- sim |>
dplyr::filter(time > 0) |>
dplyr::group_by(cohort, time) |>
dplyr::summarise(
median_Cc = median(Cc),
p05_Cc = quantile(Cc, 0.05),
p95_Cc = quantile(Cc, 0.95),
.groups = "drop"
)
ggplot(typical_summary, aes(time, median_Cc, colour = cohort, fill = cohort)) +
geom_ribbon(aes(ymin = p05_Cc, ymax = p95_Cc), alpha = 0.2, colour = NA) +
geom_line(linewidth = 0.8) +
scale_y_log10() +
scale_x_continuous(breaks = c(0, 6, 12, 24, 36, 48, 72)) +
labs(x = "Time after dose (h)", y = "Cladribine plasma conc (ng/mL)",
title = "Cladribine 10 mg oral, simulated VPC by cohort",
subtitle = "Replicates the shape of Savic 2017 Figure 2 / Figure 4",
colour = NULL, fill = NULL) +
theme_minimal() +
theme(legend.position = "bottom")
#> Warning in scale_y_log10(): log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
#> log-10 transformation introduced infinite values.
Renal-impairment exposure scaling
The Discussion of Savic 2017 reports model-predicted decreases in total cladribine clearance of 19 %, 30 %, and 40 % for CLCR = 65, 40, and 20 mL/min, respectively. Reproduce by simulating a 10 mg oral fasted dose across a CLCR grid.
ri_grid <- c(20, 40, 65, 105.2)
ri_events <- dplyr::bind_rows(lapply(seq_along(ri_grid), function(i) {
crcl <- ri_grid[i]
id_off <- (i - 1) * 1L
obs_grid <- c(seq(0, 24, by = 0.25), seq(25, 168, by = 1))
data.frame(id = c(id_off + 1L, rep(id_off + 1L, length(obs_grid))),
time = c(0, obs_grid),
evid = c(1L, rep(0L, length(obs_grid))),
amt = c(10, rep(0, length(obs_grid))),
cmt = c("depot", rep("Cc", length(obs_grid))),
CRCL = crcl,
FED = 0L,
CONMED_IFNB1A = 0L,
crcl_label = paste0("CLCR = ", crcl, " mL/min"))
}))
mod_typ <- rxode2::zeroRe(mod())
ri_sim <- as.data.frame(rxode2::rxSolve(mod_typ, events = ri_events,
keep = c("crcl_label")))
#> ℹ omega/sigma items treated as zero: 'etalka', 'etalogitf', 'etalcl_nonrenal', 'etalvc', 'etalq'
#> Warning: multi-subject simulation without without 'omega'
ri_total_cl <- ri_sim |>
dplyr::filter(time == 0.25) |> # any post-dose time works at typical values
dplyr::transmute(crcl_label, total_cl = cl) |>
dplyr::distinct()
baseline_cl <- ri_total_cl$total_cl[ri_total_cl$crcl_label == "CLCR = 105.2 mL/min"]
ri_total_cl$pct_decrease <- round(
100 * (baseline_cl - ri_total_cl$total_cl) / baseline_cl, 1)
knitr::kable(ri_total_cl,
caption = "Predicted total CL vs published Discussion targets (Savic 2017): 19 % at 65, 30 % at 40, 40 % at 20 mL/min.")| crcl_label | total_cl | pct_decrease |
|---|---|---|
| CLCR = 20 mL/min | 27.62053 | 39.4 |
| CLCR = 40 mL/min | 31.84106 | 30.2 |
| CLCR = 65 mL/min | 37.11673 | 18.6 |
| CLCR = 105.2 mL/min | 45.60000 | 0.0 |
ggplot(ri_sim, aes(time, Cc, colour = crcl_label)) +
geom_line(linewidth = 0.8) +
scale_y_log10() +
scale_x_continuous(breaks = c(0, 6, 12, 24, 48, 72, 96, 120, 168)) +
labs(x = "Time after dose (h)", y = "Cladribine plasma conc (ng/mL)",
title = "Renal-impairment exposure scaling (typical values, 10 mg oral, fasted)",
colour = NULL) +
theme_minimal() +
theme(legend.position = "bottom")
#> Warning in scale_y_log10(): log-10 transformation introduced
#> infinite values.
PKNCA validation
Use PKNCA for Cmax, Tmax, AUClast, and AUCinf on the three simulated cohorts (fasted monotherapy, fed monotherapy, fasted + IFN beta-1a). Per the source paper Table 4 footnote a, the typical-patient F and Ka used in the model imply published AUC and Cmax values consistent with the sparse-NCA values reported in the literature for cladribine 10 mg oral.
sim_nca <- sim |>
dplyr::filter(!is.na(Cc), time > 0) |>
dplyr::select(id, time, Cc, cohort)
dose_df <- events |>
dplyr::filter(evid == 1) |>
dplyr::select(id, time, amt, cohort)
conc_obj <- PKNCA::PKNCAconc(sim_nca, Cc ~ time | cohort + id,
concu = "ng/mL", timeu = "h")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | cohort + id,
doseu = "mg")
intervals <- data.frame(
start = 0,
end = Inf,
cmax = TRUE,
tmax = TRUE,
auclast = TRUE,
aucinf.obs = TRUE,
half.life = TRUE
)
nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_res <- PKNCA::pk.nca(nca_data)
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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
#> ■■■■■■■■■■■■■■■ 47% | ETA: 4s
#> 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
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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
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#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
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#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
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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
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#> Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
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#> ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 99% | ETA: 0s
#> Warning: Requesting an AUC range starting (0) before the first measurement (0.25) is not allowed
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nca_summary <- summary(nca_res)
knitr::kable(nca_summary,
caption = "Simulated NCA parameters by cohort (Savic 2017 cladribine 10 mg oral).")| Interval Start | Interval End | cohort | N | AUClast (h*ng/mL) | Cmax (ng/mL) | Tmax (h) | Half-life (h) | AUCinf,obs (h*ng/mL) |
|---|---|---|---|---|---|---|---|---|
| 0 | Inf | 10 mg oral, fasted, + IFN beta-1a | 100 | NC | 23.8 [38.9] | 0.500 [0.250, 1.50] | 22.1 [1.45] | NC |
| 0 | Inf | 10 mg oral, fasted, no IFN | 100 | NC | 23.8 [39.0] | 0.500 [0.250, 1.50] | 22.5 [1.39] | NC |
| 0 | Inf | 10 mg oral, fed, no IFN | 100 | NC | 19.3 [38.2] | 1.50 [1.50, 2.00] | 22.6 [1.38] | NC |
Comparison against published model-implied targets
Savic 2017 does not publish a per-cohort NCA table; the paper validates the model via VPCs in Figures 2-4. Three internally-consistent checks are available:
- Bioavailability ratio fed vs fasted: F(fed) / F(fasted) = 0.4 / 0.456 ~= 0.877 (paper says food reduced bioavailability by ~12 %; the model reproduces this ratio).
- IFN beta-1a effect: total CL increases by ~11 % when CONMED_IFNB1A = 1 ((22.2 + 23.4 * 1.21) / (22.2 + 23.4) ~= 1.108; paper Abstract: “an increase of 11.1 % in total clearance”).
- Renal-impairment scaling: total CL decreases by ~30 % at CLCR = 40 mL/min (paper Discussion: 30 %). See the renal-impairment table above.
Assumptions and deviations
Several simplifications were made when packaging the Savic 2017 final model. The full source-paper structure can be recovered by extending the packaged model where needed.
- Parent-only model. Savic 2017 jointly fits cladribine and its primary metabolite 2-chloroadenine (CAde). The packaged model implements the cladribine parent kinetics only. The CAde compartment was omitted because Table 4 reports CAde apparent CL/F_m and V/F_m corrected for the fraction metabolized (footnote f), and F_m is not separately identifiable in the source data. Without F_m the CAde compartment cannot be simulated on an absolute concentration scale. Users needing metabolite predictions should extend this model by adding a CAde compartment with formation rate F_m * CLNR(CdA) / Vc(CdA) and the apparent Vmax/Km saturable elimination from Table 4, acknowledging the F_m ambiguity.
-
Transit-compartment fed-state absorption simplified to a lag
time. Savic 2017 best fit the fed-state absorption with a
transit-compartment chain (mean transit time MTT = 0.910 h, n = 2.24
compartments). The packaged model approximates this with a
fed-state-only lag time alag(depot) = MTT * FED. The approximation
preserves the absorption- delay magnitude but loses the
gamma-distributed input-rate shape; the source paper notes the transit
model improved fit over a pure lag-time approach, so for downstream
simulation needing the precise absorption profile users should override
with
transit(2.24, 0.910)gated on FED. - Phase III-specific 0.319 h lag time omitted. Table 4 carries a separate 0.319 h lag time fitted only on the CLARITY (study 25643) data. This is a study-specific artefact (different sampling / dosing logistics in the larger phase III) rather than a generalizable patient-level effect; it is not reproduced here.
- Single proportional residual error magnitude. Table 4 reports four residual-error magnitudes by route/study (IV 20.0 %, oral studies 25803 34.7 %, 26127 + 26486 22.8 %, 25643 35.3 %) plus a separate BSV of 0.159 on the residual error. The packaged model uses the phase III value (35.3 %) as the largest cohort and most conservative simulation choice, and omits the BSV-on-residual term.
-
Single shared eta on distribution parameters. Table
4 reports a single BSV of 0.0365 for the four parameters Q3, Q4, V3, V4,
which is consistent with a single NONMEM ETA applied multiplicatively to
all four. The packaged model implements this via one
etalqrandom effect added to each oflq,lq2,lvp, andlvp2. Users who prefer four diagonal etas (e.g. for sensitivity analysis) can swap the shared eta foretalq ~ 0.0365,etalq2 ~ 0.0365,etalvp ~ 0.0365,etalvp2 ~ 0.0365and re-load the model. -
Logit-scale BSV on bioavailability. Savic 2017
Table 4 footnote d notes “Variance on a logit scale” for the BSV of F.
The packaged model implements this by adding
etalogitfinside the logit transform, then applying the inverse logit to keep F bounded in (0, 1). The variance 0.223 is on the logit scale, not the linear F scale. -
“Unknown” food-state records are pooled with fed
records. Table 4 reports a single “unknown/fed state” column
for Ka and F. Records in studies 26486 and 25643 that did not record
food state share parameters with the fed state. In the packaged model,
FED = 1 covers both confirmed-fed and unknown-food-state records (see
the
covariateData[[FED]]$notesfield). -
CRCL canonical column. The source paper’s CLCR (raw
Cockcroft-Gault, mL/min, not BSA-normalized) is stored under the
canonical CRCL column per
inst/references/covariate-columns.md(CRCL accepts raw Cockcroft-Gault mL/min when the paper does not apply BSA normalization). The model uses CRCL directly with reference value 105.2 mL/min (the paper’s typical patient CLCR = 6.31 L/h). -
CONMED_IFNB1A canonical covariate. Adding this
model also introduces the new canonical column CONMED_IFNB1A
(concomitant subcutaneous IFN beta-1a coadministration; binary, general
scope, reference 0 = no concomitant IFN). The register entry is
committed alongside this model in
inst/references/covariate-columns.md.