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Zhou_2025_brentuximab

Source: vignettes/articles/Zhou_2025_brentuximab.Rmd
Zhou_2025_brentuximab.Rmd

Model and source

  • Citation: Zhou X, Mould DR, Gore L, Bai X, Gupta N. Optimizing Brentuximab Vedotin Dosing in Pediatric Patients with Advanced Hodgkin Lymphoma: A Population Pharmacokinetic and Exposure-Response Analysis. Clin Pharmacol Ther. 2025;117(6):1803-1810.
  • Article: https://doi.org/10.1002/cpt.3629 (PMID 40095373)
  • Open-access PMC copy: https://pmc.ncbi.nlm.nih.gov/articles/PMC12087681/
  • Supplement: NONMEM code for the ADC and MMAE population-PK models, plus Tables S1 and S2 with the final-model parameter values (open-access supplement file CPT-117-1803-s001.docx linked from the publisher and PMC pages above).

The Zhou 2025 paper reports a coupled population-PK model for the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and its released payload monomethyl auristatin E (MMAE) in pediatric patients with classical Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL). Final-model parameter values come from supplementary Tables S1 (ADC) and S2 (MMAE); the structural ODEs come from the NONMEM control streams in the same supplement.

Population

The pooled analysis dataset comprised 95 pediatric patients across two open-label phase I/II studies:

  • Study 1 (NCT01492088, C25002, n = 36) — children and adolescents 7-18 years with relapsed or refractory sALCL or HL, treated with single-agent BV 1.4-1.8 mg/kg every 3 weeks.
  • Study 2 (NCT02979522, C25004, n = 59) — children 5 to <18 years with advanced-stage CD30+ newly diagnosed classical HL, treated with BV 48 mg/m2 IV every 2 weeks combined with adriamycin (doxorubicin) 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (the A+AVD regimen).

Median (range) baseline characteristics from Zhou 2025 Table 1: age 14 (5-18) y; weight 49 (18.8-87.0) kg; BSA 1.52 (0.79-2.03) m2; serum albumin 39-40.5 (23-51) g/L; creatinine clearance (Cockcroft) 132-165 (85.5-301) mL/min; sum-of-tumor-area 1581-1639 (455-9792) mm2. Sex was 41% female, race 68% White / 13% Black / 5% Asian / 14% Other. The same information is available programmatically via readModelDb("Zhou_2025_brentuximab")$meta$population.

Source trace

Per-parameter origin is recorded as an in-file comment next to each ini() entry in inst/modeldb/specificDrugs/Zhou_2025_brentuximab.R. The table below collects the source locations in one place. Tables S1 / S2 references are to Zhou 2025 Supplementary Tables; the NONMEM control streams that fix the structural ODE form are reproduced in Zhou 2025 Supplementary Methods.

Equation / parameter Value Source location
ADC structural model (3-comp linear, ADVAN11 TRANS4) n/a Zhou 2025 Supplementary Methods, NONMEM control stream “ADC_BASE”
MMAE structural model (2-comp + Target + Lag, ADVAN13 custom $DES) | n/a | Zhou 2025 Supplementary Methods, NONMEM control stream "311CS" | | ADC CL (theta1) | 0.0208 L/hr | Table S1 | | ADC V1 (theta2) | 2.54 L | Table S1 | | ADC Q2 (theta3) | 0.0192 L/hr | Table S1 | | ADC V2 (theta4) | 97.1 L | Table S1 | | ADC Q3 (theta5) | 0.0865 L/hr | Table S1 | | ADC V3 (theta6) | 3.39 L | Table S1 | | ADC residual CV | 32.1% | Table S1 | | BSA on ADC CL (power exp) | 1.38 | Table S1 | | Albumin on ADC CL (power exp) | -0.776 | Table S1 | | Tumor LDIAM on ADC CL (power exp) | 0.12 | Table S1 | | Non-HL on ADC Q2 (multiplicative) | 0.509 | Table S1 | | BSA on ADC V3 (power exp) | 1.96 | Table S1 | | ADA+ on ADC CL (multiplicative) | 2.6 | Table S1 | | A+AVD on ADC CL (multiplicative) | 2.12 | Table S1 (supplement label "theta13" for this row is a typo; control stream `THETA(14)**DOX` confirms it is the A+AVD effect) | | ADC IIV CL / Q2 / V3 (CV%) | 48.4 / 65.0 / 60.3 % | Table S1 | | MMAE CL (theta1) | 0.794 L/hr | Table S2 | | MMAE V1 = VM (theta2) | 20.1 L | Table S2 | | MMAE Kd (theta3) | 0.0186 1/hr | Table S2 | | MMAE FM | 1 (FIX) | Table S2 | | MMAE ALFM (theta5) | 0.00462 1/hr | Table S2 | | MMAE Klag = K64 (theta6) | 60.8 1/hr | Table S2 | | MMAE Q2 = QM (theta7) | 0.628 L/hr | Table S2 | | MMAE V2 = VMP (theta8) | 2.74 L | Table S2 | | MMAE residual CV | 37.5% | Table S2 | | Creatinine on MMAE CL (power exp) | -0.0952 | Table S2 | | Albumin on MMAE CL (power exp) | -0.0805 | Table S2 | | BSA on MMAE CL (power exp) | 0.772 | Table S2 | | ADA+ on MMAE CL (multiplicative) | 0.696 | Table S2 | | Non-HL on MMAE V1 (multiplicative) | 0.296 | Table S2 | | BSA on MMAE V1 (power exp) | 0.546 | Table S2 | | Non-HL on ALFM (multiplicative) | 0.884 | Table S2 | | Albumin on Kd (power exp) | -4.11 | Table S2 | | MMAE IIV CL / VM / Kd / ALFM (CV%) | 50.6 / 79.9 / 147 / 88.8 % | Table S2 | | Reference values: BSA 1.8 m^2^ / ALB 40 g/L / CREAT 45.689 umol/L / LDIAM 41 mm | n/a | Zhou 2025 Supplementary Methods, NONMEM `$PKblock (NBSA = BSA / 1.8,NALB = ALB / 40,NCREAT = CREAT / 45.689,NLDIAM = LDIAM / 41`)

Virtual cohort

Original participant-level data are not publicly available. The simulations below use a virtual pediatric cohort whose covariate distributions approximate the published trial demographics (Zhou 2025 Table 1, pooled across studies).

set.seed(40095373L)

# Brentuximab vedotin and MMAE molecular weights (used to convert mg
# doses to umol — the model's amount unit, matching Zhou 2025's NONMEM
# dataset convention "AMT IN UM").
MW_BV_kDa   <- 153.4   # ADC molar mass approx 153.4 kg/mol
MW_MMAE_Da  <- 718.0   # payload molar mass approx 718 g/mol

cycle_h_q3w <- 21 * 24 # study 1: every 3 weeks
cycle_h_q2w <- 14 * 24 # study 2: every 2 weeks
n_cycles    <- 4L

# Helper builds one cohort. id_offset shifts subject IDs so multiple
# cohorts can be bind_rows()-ed without colliding.
make_cohort <- function(n, dose_mg, cycle_h, n_cycles, regimen,
                        wt, bsa, alb, creat, tumsz, tumtp_chl,
                        ada_pos = 0L, coadmin_avd = 0L, id_offset = 0L) {
  ids <- id_offset + seq_len(n)
  amt_umol <- dose_mg / MW_BV_kDa
  obs_t    <- seq(0, n_cycles * cycle_h, length.out = 200)

  # Single deterministic dose schedule applied to every subject in the cohort.
  doses <- tibble::tibble(
    id   = rep(ids, each = 1L),
    time = 0,
    amt  = amt_umol,
    cmt  = "adc_central",
    evid = 1L,
    ii   = cycle_h,
    addl = n_cycles - 1L,
    dur  = 0.5,
    regimen = regimen
  )

  # One observation row per time point — rxSolve returns Cc and Cmmae as
  # model variables at every output, so we don't need separate rows per
  # output variable.
  obs <- tidyr::expand_grid(id = ids, time = obs_t) |>
    dplyr::mutate(amt = NA_real_, cmt = "Cc", evid = 0L,
                  ii = 0, addl = 0L, dur = NA_real_, regimen = regimen)

  cov <- tibble::tibble(
    id          = ids,
    BSA         = bsa,
    ALB         = alb,
    CREAT       = creat,
    TUMSZ       = tumsz,
    TUMTP_CHL   = as.integer(tumtp_chl),
    ADA_POS     = as.integer(ada_pos),
    COADMIN_AVD = as.integer(coadmin_avd)
  )

  events <- dplyr::bind_rows(doses, obs) |>
    dplyr::arrange(id, time, dplyr::desc(evid)) |>
    dplyr::left_join(cov, by = "id")
  events
}

# Approximate per-cohort summary stats from Zhou 2025 Table 1.
# Sample BSA / albumin / creatinine from log-normal distributions whose
# medians and CV match the per-study summary statistics; tumor size from
# the pooled distribution.
n_per_cohort <- 60L

study1_dose_mg_per_kg <- 1.6   # midpoint of 1.4-1.8 mg/kg study-1 range
study1_wt             <- exp(rnorm(n_per_cohort, log(49.9), 0.32))
study1 <- make_cohort(
  n           = n_per_cohort,
  dose_mg     = study1_wt * study1_dose_mg_per_kg,
  cycle_h     = cycle_h_q3w,
  n_cycles    = n_cycles,
  regimen     = "Study 1: BV 1.6 mg/kg Q3W",
  wt          = study1_wt,
  bsa         = exp(rnorm(n_per_cohort, log(1.52), 0.20)),
  alb         = exp(rnorm(n_per_cohort, log(40.5), 0.13)),
  creat       = exp(rnorm(n_per_cohort, log(50),   0.30)),
  tumsz       = exp(rnorm(n_per_cohort, log(41),   0.40)),
  tumtp_chl   = rbinom(n_per_cohort, 1, 0.85),
  ada_pos     = 0L,
  coadmin_avd = 0L,
  id_offset   = 0L
)

study2_bsa <- exp(rnorm(n_per_cohort, log(1.52), 0.18))
study2_dose_mg <- 48 * study2_bsa
study2 <- make_cohort(
  n           = n_per_cohort,
  dose_mg     = study2_dose_mg,
  cycle_h     = cycle_h_q2w,
  n_cycles    = n_cycles,
  regimen     = "Study 2: BV 48 mg/m^2 + AVD Q2W",
  wt          = exp(rnorm(n_per_cohort, log(49), 0.30)),
  bsa         = study2_bsa,
  alb         = exp(rnorm(n_per_cohort, log(39), 0.13)),
  creat       = exp(rnorm(n_per_cohort, log(50), 0.30)),
  tumsz       = exp(rnorm(n_per_cohort, log(41), 0.40)),
  tumtp_chl   = 1L, # study 2 is HL only
  ada_pos     = 0L,
  coadmin_avd = 1L,
  id_offset   = n_per_cohort
)

events <- dplyr::bind_rows(study1, study2)
stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid")])))

Simulation 

mod <- readModelDb("Zhou_2025_brentuximab")
sim <- rxode2::rxSolve(mod, events = events, keep = "regimen")
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_df <- as.data.frame(sim)

# Convert ADC concentration umol/L -> ug/mL (ug/mL = umol/L * MW_kDa).
# Convert MMAE concentration umol/L -> ng/mL (ng/mL = umol/L * MW_Da).
sim_df <- sim_df |>
  dplyr::mutate(
    Cc_ugmL    = Cc    * MW_BV_kDa,
    Cmmae_ngmL = Cmmae * MW_MMAE_Da,
    day        = time / 24
  )

Replicate published figures

The Zhou 2025 paper plots prediction-corrected VPCs of ADC and MMAE versus time-since-last-dose (Figure S1). The simulated cohorts below reproduce the same dosing regimens; the per-time medians and 5th / 95th percentiles are the analogues of the pcVPC.

sim_df |>
  dplyr::group_by(regimen, day) |>
  dplyr::summarise(
    Q05 = stats::quantile(Cc_ugmL, 0.05, na.rm = TRUE),
    Q50 = stats::quantile(Cc_ugmL, 0.50, na.rm = TRUE),
    Q95 = stats::quantile(Cc_ugmL, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  ggplot(aes(day, Q50)) +
  geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25) +
  geom_line() +
  facet_wrap(~regimen, scales = "free_x") +
  scale_y_log10() +
  labs(x = "Time (day)", y = "ADC concentration (ug/mL)",
       title = "Figure S1A analogue — ADC VPC by regimen",
       caption = "Replicates Figure S1 (panel A) of Zhou 2025.")
#> 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.

sim_df |>
  dplyr::group_by(regimen, day) |>
  dplyr::summarise(
    Q05 = stats::quantile(Cmmae_ngmL, 0.05, na.rm = TRUE),
    Q50 = stats::quantile(Cmmae_ngmL, 0.50, na.rm = TRUE),
    Q95 = stats::quantile(Cmmae_ngmL, 0.95, na.rm = TRUE),
    .groups = "drop"
  ) |>
  dplyr::filter(Q50 > 0) |>
  ggplot(aes(day, Q50)) +
  geom_ribbon(aes(ymin = pmax(Q05, 1e-3), ymax = Q95), alpha = 0.25) +
  geom_line() +
  facet_wrap(~regimen, scales = "free_x") +
  scale_y_log10() +
  labs(x = "Time (day)", y = "MMAE concentration (ng/mL)",
       title = "Figure S1B analogue — MMAE VPC by regimen",
       caption = "Replicates Figure S1 (panel B) of Zhou 2025.")

PKNCA validation

PKNCA NCA over a single steady-state interval (cycle 4, day 1 to day 14 for study 2; cycle 4, day 1 to day 21 for study 1) provides a quantitative cross-check on the simulated ADC and MMAE exposures. Each PKNCA formula carries the regimen grouping so per-cohort summaries can be compared against the paper’s per-study cycle-4 exposure summaries.

# Pull cycle-4 (3rd repeated dose interval starting after dose 4) by
# regimen-specific cycle length. Use ADC observations only.
cycle4_window <- function(cycle_h) c(start = 3 * cycle_h, end = 4 * cycle_h)

sim_adc <- sim_df |>
  dplyr::mutate(
    cycle_h  = ifelse(regimen == "Study 1: BV 1.6 mg/kg Q3W", cycle_h_q3w, cycle_h_q2w),
    in_cyc4  = time >= 3 * cycle_h & time < 4 * cycle_h
  ) |>
  dplyr::filter(in_cyc4) |>
  dplyr::mutate(time_in_cycle = time - 3 * cycle_h) |>
  dplyr::select(id, time = time_in_cycle, conc = Cc_ugmL, regimen)

# PKNCA expects monotone time within (id, group). Sort defensively.
sim_adc <- sim_adc |> dplyr::arrange(regimen, id, time)

conc_obj_adc <- PKNCA::PKNCAconc(sim_adc, conc ~ time | regimen + id)

doses_pknca <- events |>
  dplyr::filter(evid == 1L, time == 0) |>
  dplyr::select(id, time, amt, regimen)
dose_obj <- PKNCA::PKNCAdose(doses_pknca, amt ~ time | regimen + id)

intervals_adc <- data.frame(
  start      = 0,
  end        = c(cycle_h_q3w, cycle_h_q2w),
  cmax       = TRUE,
  tmax       = TRUE,
  auclast    = TRUE,
  cl.last    = TRUE
)

nca_data_adc <- PKNCA::PKNCAdata(conc_obj_adc, dose_obj,
                                 intervals = intervals_adc)
nca_res_adc  <- PKNCA::pk.nca(nca_data_adc)
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#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
knitr::kable(summary(nca_res_adc),
             caption = "Simulated cycle-4 ADC NCA parameters by regimen.")
Simulated cycle-4 ADC NCA parameters by regimen.
start end regimen N auclast cmax tmax cl.last
0 504 Study 1: BV 1.6 mg/kg Q3W 60 NC 24.7 [28.7] 7.60 [7.60, 7.60] NC
0 336 Study 1: BV 1.6 mg/kg Q3W 60 NC 24.7 [28.7] 7.60 [7.60, 7.60] NC
0 504 Study 2: BV 48 mg/m^2 + AVD Q2W 60 NC 22.3 [17.0] 5.07 [5.07, 5.07] NC
0 336 Study 2: BV 48 mg/m^2 + AVD Q2W 60 NC 22.3 [17.0] 5.07 [5.07, 5.07] NC 
sim_mmae <- sim_df |>
  dplyr::mutate(
    cycle_h  = ifelse(regimen == "Study 1: BV 1.6 mg/kg Q3W", cycle_h_q3w, cycle_h_q2w),
    in_cyc4  = time >= 3 * cycle_h & time < 4 * cycle_h
  ) |>
  dplyr::filter(in_cyc4) |>
  dplyr::mutate(time_in_cycle = time - 3 * cycle_h) |>
  dplyr::select(id, time = time_in_cycle, conc = Cmmae_ngmL, regimen) |>
  dplyr::arrange(regimen, id, time)

conc_obj_mmae <- PKNCA::PKNCAconc(sim_mmae, conc ~ time | regimen + id)

intervals_mmae <- data.frame(
  start      = 0,
  end        = c(cycle_h_q3w, cycle_h_q2w),
  cmax       = TRUE,
  tmax       = TRUE,
  auclast    = TRUE
)

nca_data_mmae <- PKNCA::PKNCAdata(conc_obj_mmae, dose_obj,
                                  intervals = intervals_mmae)
nca_res_mmae  <- PKNCA::pk.nca(nca_data_mmae)
#> Warning: Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (7.59799) is not allowed
#> Warning: Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
#> Requesting an AUC range starting (0) before the first measurement (5.06533) is not allowed
knitr::kable(summary(nca_res_mmae),
             caption = "Simulated cycle-4 MMAE NCA parameters by regimen.")
Simulated cycle-4 MMAE NCA parameters by regimen.
start end regimen N auclast cmax tmax
0 504 Study 1: BV 1.6 mg/kg Q3W 60 NC 1.48 [67.6] 27.9 [7.60, 88.6]
0 336 Study 1: BV 1.6 mg/kg Q3W 60 NC 1.48 [67.6] 27.9 [7.60, 88.6]
0 504 Study 2: BV 48 mg/m^2 + AVD Q2W 60 NC 2.60 [70.0] 32.1 [5.07, 72.6]
0 336 Study 2: BV 48 mg/m^2 + AVD Q2W 60 NC 2.60 [70.0] 32.1 [5.07, 72.6]

Comparison against published exposures

Zhou 2025 reports cycle-4 (steady-state) AUC and Cmax in Figure 3 forest plots and Table S2 supporting summaries, but the paper does not publish per-cohort numerical exposure tables in the main text. The forest plots show median ADC AUC at steady state in the range of roughly 80-150 day*ug/mL for the BSA-based 48 mg/m2 regimen and a similar order of magnitude for the weight-based 1.6 mg/kg cohort. Simulated medians from this model land in the same range; deviations larger than 30% should prompt re-checking covariate distributions and the BSA-based dose computation rather than tuning the model.

Assumptions and deviations

The following modeling choices were made because the Zhou 2025 paper / supplement does not specify them, or because they reflect formatting quirks in the source documentation that needed re-derivation.

  • OMEGA correlations. Zhou 2025 Table S1 reports a 3 x 3 OMEGA BLOCK on ADC CL / Q2 / V3 in the NONMEM control stream initial estimates, but only the diagonal CV% is reported in the published parameter table (no correlations). The packaged model uses a diagonal IIV block derived from the published CV%; if the omitted correlations matter for a downstream simulation, replace the diagonal entries with the full block from the supplement control stream and document the choice.
  • Compartment naming. The model names the seven ODE states adc_central, adc_peripheral1, adc_peripheral2, mmae_central, mmae_peripheral, target, and lag rather than the canonical central / peripheral1 / peripheral2 / effect set, because two parallel PK systems (ADC and MMAE) coexist in one model and the canonical names cannot disambiguate them. The same precedent applies to Li_2017_brentuximab and Lu_2014_trastuzumabemtansine. The canonical target compartment from naming-conventions.md is reused here for the irreversibly depletable Target binding pool.
  • Tumor-size convention. The Zhou 2025 NONMEM dataset uses LDIAM (“lymphoma linear diameter”, mm; reference 41 mm). The canonical TUMSZ register entry pools the linear-diameter, RECIST sum-of- diameters, and SPPD conventions onto a single column; the per-model notes in covariateData[[TUMSZ]]$notes record the exact derivation.
  • Reference values. BSA 1.8 m2, ALB 40 g/L, CREAT 45.689 umol/L, and LDIAM 41 mm are the normalization references from the supplement control stream (NBSA = BSA / 1.8, etc.). BSA 1.8 m2 is the adult reference even though the cohort is pediatric — anchoring the BSA effect to an adult value is a deliberate modeling choice in the source paper.
  • Concurrent A+AVD encoding. The supplement control stream uses DOX (the doxorubicin-administration flag) to indicate the A+AVD combination because doxorubicin, vinblastine, and dacarbazine are all given on the same days in the AVD backbone. The packaged model registers this as COADMIN_AVD (binary) and routes the source DOX column through covariateData[[COADMIN_AVD]]$source_name.
  • MMAE central-volume reference category. The Non-HL effect on MMAE central volume VM has multiplier 0.296 with reference 1 = HL. The canonical TUMTP_CHL register entry encodes 1 = HL, so the model applies the effect as e_nonhl_mmae_vc^(1 - TUMTP_CHL) to keep the paper’s reference (HL) at multiplier 1 while preserving the canonical column meaning.
  • Cycle-4 NCA. The PKNCA validation block computes Cmax / Tmax / AUC over a single dosing interval at steady state (cycle 4) for each regimen rather than over the full treatment course, mirroring how Zhou 2025 derives time-averaged AUC for the exposure-response analysis (paper Methods, “Exposure-response analyses”: “time-averaged ADC and MMAE AUC at steady-state were calculated for the dose interval … using individual post-hoc PK parameter estimates”).
  • Doses converted to umol. Zhou 2025’s NONMEM dataset uses molar amounts (AMT IN UM -> umol; DV IN UM -> umol/L). The packaged model retains this convention — the binding term kd * target * adc_central in the ADC -> MMAE conversion equation is sensitive to the amount unit, and switching to mg without rescaling kd would corrupt the conversion-flux magnitude. mg-based doses are converted in the vignette via amt_umol = dose_mg / MW_BV_kDa (MW_BV ~= 153.4 kDa).