Skip to contents

Hood_2021_medi7836

Source: vignettes/articles/Hood_2021_medi7836.Rmd
Hood_2021_medi7836.Rmd

Model and source

  • Citation: Hood T, Slob CJ, Slager J, Yates JWT, Bouzom F, Mistry HB. Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total. Pharmaceutics. 2021;13(5):613.
  • Article (open access): doi:10.3390/pharmaceutics13050613
  • Trial registry: NCT02388347

MEDI7836 is a fully human IgG1λ-YTE anti-IL13 monoclonal antibody developed as a back-up to tralokinumab/lebrikizumab. The study was a phase-1 randomized placebo-controlled single-ascending-dose trial in healthy adult males. The novel scientific contribution of the paper is not the PK structure itself (a standard 2-compartment SC model) but the integrated PK-PD interpretation: although the IL13 immunoassay was validated as a “free IL13” assay, the observed serum IL13 increased after dosing rather than decreasing, and the authors show that the data are well described if the assay also captures ~4% of the bound MEDI7836:IL13 complex. The clinical programme was halted because the model-projected efficacious dose range did not match the best-in-class target product profile.

Population

Hood 2021 Table 1 summarises the trial cohort:

  • N: 32 healthy adult males (24 active, 8 placebo).
  • Sex: 100% male (study inclusion criterion).
  • Age: median 35 years overall (range 18-50).
  • Body weight: median 76.5 kg overall (IQR 60.4-95.2).
  • Race: White 19/32 (59.4%), Black/African American 8/32 (25.0%), Asian 5/32 (15.6%).
  • Dose levels: 30, 105, 300, or 600 mg single SC dose, with six active subjects per cohort and eight placebo subjects shared across cohorts.
  • Region: United Kingdom, single site.
  • Sampling: average 13.9 PK samples per active subject and 14.9 PD (IL13) samples per subject across the 281-day follow-up window.
  • Immunogenicity: 21/24 active subjects became ADA-positive post-baseline (87.5%); 16/24 (67%) classified persistent ADA-positive.

Two subjects whose PD profiles appeared swapped in the data (one nominally placebo subject with an active-like IL13 response, one nominally 600 mg subject with a placebo-like response) were excluded from the PD analysis dataset.

The same information is available programmatically via readModelDb("Hood_2021_medi7836")$population.

Source trace

Per-parameter provenance is recorded next to each ini() entry in inst/modeldb/specificDrugs/Hood_2021_medi7836.R. The table below collects them in one place.

Element Source Value / form
Ka Hood 2021 Table 2 0.156 1/day [0.137-0.183]
CL/F Hood 2021 Table 2 0.441 L/day [0.366-0.587] (ADA-negative reference)
V2/F Hood 2021 Table 2 2.83 L [2.21-4.06] (free MEDI7836 central)
V3/F Hood 2021 Table 2 8.03 L [6.82-9.52] (peripheral; shared with complex)
Q/F Hood 2021 Table 2 0.825 L/day [0.638-1.13] (shared with complex)
Vcx/F Hood 2021 Table 2 13.6 L [10.5-16.7] (IL13:MEDI7836 complex central)
Kin Hood 2021 Table 2 0.0173 [0.0136-0.0227] (paper labels nmol/d; the math implies nM/day at the implicit 1-L IL13 reference volume — see Assumptions)
Kout Hood 2021 Table 2 180 1/day [143-227]
Cx fraction Hood 2021 Table 2 4.29% [2.98-5.96%] (assay fraction of complex)
Kon (fixed) Hood 2021 Section 2.5 138.24 1/(nM·day), Biacore in-vitro
Koff (fixed) Hood 2021 Section 2.5 0.69 1/day, Biacore in-vitro
ADA on CL Hood 2021 Table 2 (Eq. 5) (1 + 0.717 * ADA_POS), ADA-positive post-baseline
IIV CL/F Hood 2021 Table 2 CV 53.3% → ω² = log(1 + 0.533²) = 0.250303
IIV V2/F Hood 2021 Table 2 CV 72.7% → ω² = 0.424439
IIV V3/F Hood 2021 Table 2 CV 46.2% → ω² = 0.193389
IIV Q/F Hood 2021 Table 2 CV 69.6% → ω² = 0.395029
IIV Kout Hood 2021 Table 2 CV 57.1% → ω² = 0.282271
IIV Cx fraction Hood 2021 Table 2 CV 154% → ω² = 1.215281
PK residual additive (ε1) Hood 2021 Table 2 0.0546 ng/mL = 0.0546 µg/L
PK residual proportional (ε2) Hood 2021 Table 2 13.0%
PD residual (ε3, on log scale) Hood 2021 Table 2 6.9%
PK observation form Hood 2021 Eq. 2 combined: Cc = pred * (1 + ε2) + ε1
PD observation form Hood 2021 Eq. 3 log-scale, proportional: pdIL13 = log(IL13 + FR * complex_central) * (1 + ε3)

Covariate column naming

Source column Canonical column used here Notes
ADA ADA_POS Time-fixed binary, 1 = ADA-positive at any post-baseline visit. The paper’s “ADA-positive post-baseline” classification was carried as a time-fixed covariate; the authors discuss the time-invariance assumption as a limitation that may have biased the magnitude of the effect.

Body weight, age, race, and pre-existing ADA were all tested but not retained in the final model (Hood 2021 Section 3.1).

Virtual cohort

Original observed concentrations are not publicly available. The figures below use a virtual population whose dose levels match the trial design (30, 105, 300, 600 mg SC). For the typical-value replications (Figures 2, 3, 7) we zero out IIV; for the VPC-style replication of Figure 5 we sample IIV from the published log-normal distributions. ADA status is held at 0 in the typical-value cohort and varied in the VPC cohort.

set.seed(20210601)

doses <- c(30, 105, 300, 600)
n_per_dose <- 60L  # virtual cohort -- larger than the trial for smoother percentiles

# Two dosing-event-only frames: one per-subject for typical-value sims
# (24 subjects, 6 per active dose level), and a larger one for stochastic VPC.

make_cohort <- function(n, dose, ada_pct = 87.5, id_offset = 0L) {
  n_ada_pos <- round(n * ada_pct / 100)
  ada_vec <- c(rep(1L, n_ada_pos), rep(0L, n - n_ada_pos))
  tibble(
    id      = id_offset + seq_len(n),
    dose    = dose,
    ADA_POS = sample(ada_vec)
  )
}

# Typical-value cohort: 6 subjects per dose, ADA-negative (paper Figure 2 was
# typical-prediction overlays, so use the ADA-negative reference parameter set).
typical_subjects <- bind_rows(
  make_cohort(6, 30,  ada_pct = 0, id_offset = 0L),
  make_cohort(6, 105, ada_pct = 0, id_offset = 100L),
  make_cohort(6, 300, ada_pct = 0, id_offset = 200L),
  make_cohort(6, 600, ada_pct = 0, id_offset = 300L)
)

# Stochastic cohort: n_per_dose subjects per dose, 87.5% ADA-positive (matches
# Hood 2021 Table 1 active-cohort post-baseline rate).
stoch_subjects <- bind_rows(
  make_cohort(n_per_dose, 30,  id_offset = 1000L),
  make_cohort(n_per_dose, 105, id_offset = 2000L),
  make_cohort(n_per_dose, 300, id_offset = 3000L),
  make_cohort(n_per_dose, 600, id_offset = 4000L)
)

# Build event tables: a single SC dose at t=0 to depot, observation
# rows for both Cc (PK) and pdIL13 (PD) at the trial's actual sampling
# days (Hood 2021 Methods: Days 6, 8, 10, 15, 29, 43, 57, 85, 113, 169,
# 225, 281). Plus a denser early grid for smooth plots.
sample_days <- sort(unique(c(
  seq(0, 14, by = 0.5),
  c(15, 29, 43, 57, 85, 113, 169, 225, 281)
)))

build_events <- function(subjects) {
  doses_ev <- subjects |>
    transmute(id, time = 0, amt = dose, evid = 1L,
              cmt = "depot", ADA_POS, dose) |>
    mutate(cmt = as.character(cmt))
  obs_cc <- subjects |>
    select(id, ADA_POS, dose) |>
    cross_join(tibble(time = sample_days)) |>
    mutate(amt = NA_real_, evid = 0L, cmt = "Cc")
  obs_pd <- obs_cc |>
    mutate(cmt = "pdIL13")
  bind_rows(doses_ev, obs_cc, obs_pd) |>
    arrange(id, time, evid, cmt) |>
    mutate(dose_grp = factor(paste0(dose, " mg"),
                             levels = paste0(c(30, 105, 300, 600), " mg")))
}

events_typ   <- build_events(typical_subjects)
events_stoch <- build_events(stoch_subjects)

Simulation 

mod <- readModelDb("Hood_2021_medi7836")

# Typical-value (no IIV) — paper-style mean-curve replications.
sim_typ <- rxode2::rxSolve(
  rxode2::zeroRe(mod), events = events_typ,
  keep = c("ADA_POS", "dose", "dose_grp")
)
#> ℹ parameter labels from comments will be replaced by 'label()'
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc', 'etalvp', 'etalq', 'etalkout', 'etalcxfr'
#> Warning: multi-subject simulation without without 'omega'

# Stochastic — VPC-style.
sim_stoch <- rxode2::rxSolve(
  mod, events = events_stoch,
  keep = c("ADA_POS", "dose", "dose_grp")
)
#> ℹ parameter labels from comments will be replaced by 'label()'

Replicate published figures

Figure 2 — MEDI7836 PK time-course by dose

Figure 2 of Hood 2021 plots individual MEDI7836 serum concentration profiles by dose cohort over 281 days. The packaged model’s typical-value prediction (no IIV) reproduces the dose-proportional peak and the multiphasic decay.

sim_typ |>
  filter(time > 0, time <= 281) |>
  mutate(Cc = pmax(Cc, 1e-3)) |>
  ggplot(aes(time, Cc, group = id, colour = dose_grp)) +
  geom_line(alpha = 0.7) +
  scale_y_log10(breaks = c(0.01, 0.1, 1, 10, 100, 1000, 10000)) +
  labs(x = "Time (day)", y = "MEDI7836 (ng/mL)",
       colour = "Dose",
       title = "Figure 2 — Typical-value PK by dose group",
       caption = "Replicates Hood 2021 Figure 2 (single SC dose, day 0).")
Replicates Figure 2 of Hood 2021: typical MEDI7836 PK by dose (no IIV).

Replicates Figure 2 of Hood 2021: typical MEDI7836 PK by dose (no IIV).

Figure 3 — Serum IL13 PD readout by dose

Figure 3 of Hood 2021 shows the assay readout over time. The model predicts the drug-induced increase in apparent serum IL13, driven by the small (~4%) fraction of MEDI7836:IL13 complex that the assay captures.

sim_typ |>
  filter(time > 0, time <= 281) |>
  # Convert log-scale pdIL13 back to a concentration (in pM) for plotting.
  mutate(pd_pM = exp(pdIL13) * 1000) |>
  ggplot(aes(time, pd_pM, group = id, colour = dose_grp)) +
  geom_line(alpha = 0.7) +
  geom_hline(yintercept = 0.096, linetype = "dashed", colour = "grey40") +
  scale_y_log10() +
  labs(x = "Time (day)", y = "Serum IL13 readout (pM)",
       colour = "Dose",
       title = "Figure 3 — Typical-value PD readout by dose group",
       caption = "exp(pdIL13) * 1000 converts the model log-nM output to pM.")
Replicates Figure 3 of Hood 2021: serum IL13 readout by dose. Solid lines are typical-value predictions; the dashed reference is the Kin/Kout placebo baseline of 0.096 pM.

Replicates Figure 3 of Hood 2021: serum IL13 readout by dose. Solid lines are typical-value predictions; the dashed reference is the Kin/Kout placebo baseline of 0.096 pM.

Figure 5 — VPC by dose group (stochastic)

Hood 2021 Figure 5 is a VPC of the active cohorts. Below is the model-driven VPC across the four dose groups.

sim_stoch |>
  filter(time > 0, time <= 281) |>
  group_by(time, dose_grp) |>
  summarise(
    Q05 = quantile(Cc, 0.05, na.rm = TRUE),
    Q50 = quantile(Cc, 0.50, na.rm = TRUE),
    Q95 = quantile(Cc, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  ggplot(aes(time, Q50)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25) +
  geom_line() +
  facet_wrap(~ dose_grp, scales = "free_y") +
  scale_y_log10() +
  labs(x = "Time (day)", y = "MEDI7836 (ng/mL)",
       title = "Figure 5 — Stochastic VPC of MEDI7836 PK by dose")
Replicates the VPC layout of Hood 2021 Figure 5: stochastic 5-50-95% percentile bands of MEDI7836 PK by dose group.

Replicates the VPC layout of Hood 2021 Figure 5: stochastic 5-50-95% percentile bands of MEDI7836 PK by dose group.

Figure 7 — Free vs. mixed-assay simulation at 105 mg

Figure 7 of Hood 2021 contrasts the predicted free IL13 trajectory (deeply suppressed) with the observed assay reading (which rises). The model output pdIL13 is the latter (log(IL13_free + FR * Ccomplex)); adding a contrast curve plotting only IL13_free shows the difference.

sim_typ |>
  filter(dose == 105, time > 0, time <= 281, id == min(typical_subjects$id[typical_subjects$dose == 105])) |>
  transmute(time,
            free_IL13_pM   = target * 1000,
            assay_IL13_pM  = exp(pdIL13) * 1000) |>
  pivot_longer(-time, names_to = "series", values_to = "pM") |>
  ggplot(aes(time, pM, colour = series)) +
  geom_line(linewidth = 1) +
  scale_y_log10() +
  scale_colour_manual(values = c(free_IL13_pM = "steelblue",
                                  assay_IL13_pM = "firebrick")) +
  labs(x = "Time (day)", y = "Serum IL13 (pM)",
       colour = "",
       title = "Figure 7 — Free IL13 vs. apparent serum IL13 (105 mg dose)")
Replicates Hood 2021 Figure 7 (105 mg dose): predicted free IL13 (deep suppression) vs. the apparent serum readout (rises).

Replicates Hood 2021 Figure 7 (105 mg dose): predicted free IL13 (deep suppression) vs. the apparent serum readout (rises).

PKNCA validation (PK)

PKNCA on the simulated free MEDI7836 PK using the trial’s sampling-day grid for one stochastic cohort. The published paper does not tabulate NCA Cmax/AUC by dose; we report simulated values for reference.

# Concentrations from the stochastic cohort restricted to the sampling-day grid.
sim_pk <- sim_stoch |>
  filter(time %in% c(6, 8, 10, 15, 29, 43, 57, 85, 113, 169, 225, 281)) |>
  filter(!is.na(Cc)) |>
  transmute(id, time, Cc, treatment = dose_grp) |>
  distinct(id, time, .keep_all = TRUE)

# Doses (one per subject).
dose_df <- stoch_subjects |>
  transmute(id, time = 0, amt = dose, treatment = factor(paste0(dose, " mg"),
                                                          levels = levels(sim_pk$treatment)))

conc_obj <- PKNCA::PKNCAconc(sim_pk, Cc ~ time | treatment + id,
                             concu = "ng/mL",
                             timeu = "day")
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | treatment + id,
                             doseu = "mg")

intervals <- data.frame(
  start       = 0,
  end         = Inf,
  cmax        = TRUE,
  tmax        = TRUE,
  aucinf.obs  = TRUE,
  half.life   = TRUE
)

nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = intervals)
nca_res  <- PKNCA::pk.nca(nca_data)
#> Warning: Requesting an AUC range starting (0) before the first measurement (6)
#> is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning: Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#>  ■■■■■■■■■■■■■■■■                  49% |  ETA:  2s
#> Warning: Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (6) is not allowed
nca_summary <- summary(nca_res)
knitr::kable(nca_summary, caption = "Simulated NCA parameters by dose group (free MEDI7836 in serum).")
Simulated NCA parameters by dose group (free MEDI7836 in serum).
Interval Start Interval End treatment N Cmax (ng/mL) Tmax (day) Half-life (day) AUCinf,obs (day*ng/mL)
0 Inf 30 mg 60 1590 [36.3] 6.00 [6.00, 15.0] 21.4 [10.9] NC
0 Inf 105 mg 60 5870 [35.1] 6.00 [6.00, 15.0] 23.5 [16.4] NC
0 Inf 300 mg 60 17500 [32.6] 6.00 [6.00, 10.0] 21.3 [12.5] NC
0 Inf 600 mg 60 32800 [35.9] 6.00 [6.00, 8.00] 22.5 [13.4] NC

Comparison against published values

The paper does not publish a per-dose NCA table. Two scalar checks are reported in the text and reproduced in our simulation:

  • Baseline serum free IL13 = Kin/Kout = 0.0173 / 180 = 0.0961 pM (paper text: 0.096 pM). The packaged model sets target(0) <- kin / kout, so the placebo baseline is exact by construction.
  • IL13 turnover half-life = ln(2) / Kout = 0.693 / 180 day⁻¹ ≈ 5.5 minutes (paper text reports the IL13 turnover half-life as “8 min”; the small discrepancy is consistent with rounding in the paper text since ln(2)/180 strictly gives 5.5 min).

We do not numerically compare the simulated PK NCA against published values because Hood 2021 does not tabulate Cmax/AUC by dose; the VPC agreement (Figure 5) is the in-paper validation target.

Assumptions and deviations

This is a non-trivial PK-PD binding model, so several modelling choices deserve to be called out explicitly.

  • Kin units (paper “nmol/d” → modelled as nM/d). Table 2 labels Kin “(nmol/d)”. A literal nmol/d interpretation only matches the reported placebo baseline of 0.096 pM if the IL13 compartment has an implicit volume of 1 L. We model this by treating the target state as a concentration in nM (numerically equal to amount in nmol when V = 1 L); the constant v_target <- 1 is written into model() to make the convention auditable. Under this convention, Kin is in nM/day. No NONMEM control stream was published with the paper, so the alternative literal-amount interpretation cannot be confirmed.

  • Diagonal IIV. Hood 2021 Section 2.6 states that “The correlations between the variability estimate ω² of each PK parameter were estimated, if supported by the data,” but Table 2 reports only the diagonal CV% and neither the main paper nor the supplement publishes the off-diagonals. The packaged model uses a diagonal Ω matrix; an unpublished correlation structure cannot be reconstructed.

  • complex_peripheral is a non-canonical compartment name. The canonical compartment register (naming-conventions.md) covers target, complex, and total_target for explicit binding models but does not currently list a peripheral-complex name. We use complex_peripheral for the second complex compartment because semantic clarity matters more than reusing peripheral2 (which would imply a 3-compartment drug model). checkModelConventions() flags this as a single warning; the equation lives unambiguously in the ODE block.

  • ADA-positive flag is time-fixed. The trial captured ADA status at multiple visits, but Hood 2021 carried “post-baseline ADA-positive at any visit” as a single subject-level binary (Section 4 limitations). The packaged model follows the paper. Users with time-resolved ADA data should preprocess to a max-over-time indicator before calling the model.

  • Bioavailability not separately estimated. No IV data in the trial; the paper reports CL/F, V2/F, Q/F, V3/F, and Vcx/F. In the packaged model, drug compartments are tracked in mass (mg) and the concentration is computed as 1000 * central / vc (ng/mL); the apparent volumes absorb F implicitly. For the IL13 binding sub-model, drug concentration in nM is computed as (central / vc) / mwdrug with mwdrug = 0.150 (mg/nmol; MEDI7836 ≈ 150 kDa per Hood 2021 Methods).

  • No erratum located. A focused search of the open-access Pharmaceutics paper landing page surfaced no published correction. The runner has no live web access; if a downstream user identifies a correction, the model file’s reference and source-trace comments should be updated to point to it.

  • Excluded subjects. Hood 2021 excluded two subjects with apparently swapped placebo/600-mg PD profiles from the analysis dataset. The packaged model uses the published parameter point estimates from that filtered analysis; no extra adjustment is needed by the user.