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Vancomycin (Grimsley 1999)

Source: vignettes/articles/Grimsley_1999_vancomycin.Rmd
Grimsley_1999_vancomycin.Rmd

Model and source

  • Citation: Grimsley C, Thomson AH. Pharmacokinetics and dose requirements of vancomycin in neonates. Arch Dis Child Fetal Neonatal Ed. 1999;81(3):F221-F227. doi:10.1136/fn.81.3.f221
  • Description: One-compartment IV-infusion population PK model for vancomycin in neonates and young infants (Grimsley 1999). Developed from routine therapeutic-drug-monitoring data in 59 neonates (347 concentrations). Clearance scales linearly with body weight and inversely with serum creatinine concentration (CL = 3.56 * WT / CREAT, L/h, WT in kg, CREAT in umol/L); central volume scales linearly with body weight (V = 0.669 * WT, L/kg). The covariate-coupled CL form (no separately estimated exponents) is reported by the paper as the entire structural model.
  • Article: Arch Dis Child Fetal Neonatal Ed 1999;81(3):F221-F227

Population

The model was developed from 347 routine therapeutic-drug-monitoring vancomycin concentrations in 59 neonates and young infants at Yorkhill Hospitals’ neonatal intensive care wards (Glasgow) over 64 courses of treatment (Grimsley 1999 Table 2). Postconceptual age ranged from 26-45 weeks (median 32), postnatal age 2-76 days (median 19), body weight 0.57-4.23 kg (median 1.52), and serum creatinine 18-172 umol/L (median 49). 36% of subjects were female; 85% had confirmed infection; 20% had a cardiac defect; 61% required oxygen or active ventilation. Starting doses were 15 mg/kg every 24, 12 or 8 hours given as 1-hour infusions per the Guy’s, St Thomas’s and Lewisham Hospitals Paediatric Formulary; of 347 measured concentrations, 153 were peaks (1 hour after end of infusion), 183 were troughs (end of dose interval), and 11 were mid-dose samples. The same information is available programmatically via readModelDb("Grimsley_1999_vancomycin")$population.

Source trace

Every numeric value in ini() carries an in-file comment pointing to the Grimsley 1999 source location. The table below collects them in one place for review.

Equation / parameter Value Source location
lcl (CL coefficient) 3.56 Table 4, row “Clearance (l/h)” final-model column: CL = 3.56 * WT / CREAT (SE 3.8%)
lvc (V per kg) 0.669 L/kg Table 4, row “Volume (l)” final-model column: V = 0.669 * WT (SE 4.7%)
etalcl (22% CV) 0.04729 Table 4, row “Interpatient variability on clearance” final-model column (SE 28%)
etalvc (18% CV) 0.03188 Table 4, row “Interpatient variability on volume” final-model column (SE 46%)
addSd 4.53 mg/L Table 4, row “Residual error on concentration (mg/l)” final-model column (SE 13%)
1-cmt IV-infusion structure n/a Results paragraph “When the basic structural models were compared”; Methods
Additive residual error n/a Results: “Residual error was best described by an additive structure”
CL = 3.56 * WT / CREAT n/a Results equation just before Figure 3; Table 4 footnote
V = 0.669 * WT n/a Results equation just before Figure 3; Table 4 footnote
Cohort medians (WT, CREAT) 1.52 kg, 49 umol/L Table 2 “Median (range)” column

Virtual cohort

Original observed data are not publicly available. The cohort below covers the four scenarios highlighted by Grimsley 1999 Table 5 (the final dosing nomogram). The reference scenario uses the typical neonate at the cohort median weight (1.52 kg) with serum creatinine held at 45 umol/L, dosed at 15 mg/kg every 12 hours – the exact patient described in Figure 3. Three additional scenarios sweep the nomogram-relevant creatinine range (20, 80, 120 umol/L) so the steady-state peak / trough behaviour can be compared against the target ranges Grimsley 1999 Results used to construct Table 5.

set.seed(19990901)

n_sub <- 60L

make_cohort <- function(label, wt_kg, creat_umol, dose_mg_kg, tau_h, id_offset) {
  ids <- id_offset + seq_len(n_sub)

  dose_amt_mg <- dose_mg_kg * wt_kg
  infusion_h  <- 1
  n_doses     <- 12  # 6 days of q12h dosing -- enough for steady state given t1/2 ~ 6 h

  dose_times <- seq(0, by = tau_h, length.out = n_doses)
  dose_rows <- tidyr::expand_grid(id = ids, time = dose_times) |>
    mutate(
      evid   = 1L,
      amt    = dose_amt_mg,
      cmt    = "central",
      rate   = dose_amt_mg / infusion_h,
      cohort = label,
      WT     = wt_kg,
      CREAT  = creat_umol
    )

  # Coarse buildup grid + dense final-interval grid for Cmax / Cmin resolution.
  obs_times <- sort(unique(c(
    seq(0, infusion_h * 2, by = 0.25),
    seq(0, max(dose_times), by = 1),
    seq(max(dose_times), max(dose_times) + tau_h, by = 0.25)
  )))
  obs_rows <- tidyr::expand_grid(id = ids, time = obs_times) |>
    mutate(
      evid   = 0L,
      amt    = 0,
      cmt    = NA_character_,
      rate   = 0,
      cohort = label,
      WT     = wt_kg,
      CREAT  = creat_umol
    )

  bind_rows(dose_rows, obs_rows) |> arrange(id, time, desc(evid))
}

events <- bind_rows(
  make_cohort("creat_20_q12",  1.52, 20,  15, 12, id_offset =    0L),
  make_cohort("creat_45_q12",  1.52, 45,  15, 12, id_offset = 1000L),
  make_cohort("creat_80_q12",  1.52, 80,  15, 24, id_offset = 2000L),
  make_cohort("creat_120_q12", 1.52, 120, 15, 24, id_offset = 3000L)
)

stopifnot(!anyDuplicated(unique(events[, c("id", "time", "evid")])))

Simulation 

mod <- readModelDb("Grimsley_1999_vancomycin")

sim <- rxode2::rxSolve(
  mod,
  events = events,
  keep   = c("cohort", "WT", "CREAT")
) |> as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'

For the Figure 3 typical-value replication, also simulate with the random effects zeroed:

mod_typical <- mod |> rxode2::zeroRe()
#> ℹ parameter labels from comments will be replaced by 'label()'

sim_typical <- rxode2::rxSolve(
  mod_typical,
  events = events,
  keep   = c("cohort", "WT", "CREAT")
) |> as.data.frame()
#> ℹ omega/sigma items treated as zero: 'etalcl', 'etalvc'
#> Warning: multi-subject simulation without without 'omega'

Replicate published figures

Figure 3 - typical profile with 67% interval, CREAT = 45 umol/L

Grimsley 1999 Figure 3 shows the typical population profile and 67% confidence intervals for a patient with serum creatinine 45 umol/L given vancomycin 15 mg/kg every 12 hours. The replication below shows the final dosing interval (a steady-state q12h window) with the typical-value line overlaid on the inter-individual 67% interval (16.5th-83.5th percentiles) computed from the stochastic simulation.

ss_window_start <- max(events$time[events$evid == 1 & events$cohort == "creat_45_q12"])
ss_window_end   <- ss_window_start + 12

stochastic_ribbon <- sim |>
  filter(cohort == "creat_45_q12",
         time >= ss_window_start, time <= ss_window_end) |>
  mutate(time_in_tau = time - ss_window_start) |>
  group_by(time_in_tau) |>
  summarise(
    q165 = quantile(Cc, 0.165, na.rm = TRUE),
    q500 = quantile(Cc, 0.500, na.rm = TRUE),
    q835 = quantile(Cc, 0.835, na.rm = TRUE),
    .groups = "drop"
  )

typical_line <- sim_typical |>
  filter(cohort == "creat_45_q12",
         time >= ss_window_start, time <= ss_window_end) |>
  mutate(time_in_tau = time - ss_window_start)

ggplot() +
  geom_ribbon(data = stochastic_ribbon,
              aes(x = time_in_tau, ymin = q165, ymax = q835),
              alpha = 0.25, fill = "steelblue") +
  geom_line(data = typical_line,
            aes(x = time_in_tau, y = Cc), colour = "steelblue", size = 0.9) +
  geom_hline(yintercept = 5,  linetype = "dashed", colour = "grey50") +
  geom_hline(yintercept = 12, linetype = "dashed", colour = "grey50") +
  geom_hline(yintercept = 25, linetype = "dotted",  colour = "grey50") +
  geom_hline(yintercept = 40, linetype = "dotted",  colour = "grey50") +
  labs(
    x = "Time within steady-state dosing interval (h)",
    y = "Vancomycin concentration (mg/L)",
    title = "Figure 3 replication",
    caption = "Typical 1.52-kg neonate, CREAT = 45 umol/L, 15 mg/kg q12h IV (1 h infusion). Ribbon = 67% inter-individual interval (16.5-83.5%). Dashed lines = target trough 5-12 mg/L; dotted lines = target peak 25-40 mg/L. Replicates Grimsley 1999 Figure 3."
  )
#> Warning: Using `size` aesthetic for lines was deprecated in ggplot2 3.4.0.
#> ℹ Please use `linewidth` instead.
#> This warning is displayed once per session.
#> Call `lifecycle::last_lifecycle_warnings()` to see where this warning was
#> generated.

PKNCA validation

The block below computes steady-state peak, trough and AUC0-tau over the final dosing interval and compares against the trough target range 5-12 mg/L and peak target range 25-40 mg/L that Grimsley 1999 used to define the dose nomogram in Table 5. The treatment grouping is cohort, with one cohort per Table 5 creatinine band tested.

# Per-cohort steady-state interval (final dose to final dose + tau).
# tau is the spacing between the last two dose times within each cohort.
ss_windows <- events |>
  filter(evid == 1) |>
  group_by(cohort) |>
  summarise(
    start_ss = max(time),
    tau      = max(time) - sort(unique(time), decreasing = TRUE)[2],
    .groups  = "drop"
  ) |>
  mutate(end_ss = start_ss + tau)

sim_nca <- sim |>
  filter(!is.na(Cc)) |>
  inner_join(ss_windows |> select(cohort, start_ss, end_ss), by = "cohort") |>
  filter(time >= start_ss, time <= end_ss) |>
  select(id, time, Cc, cohort)

dose_df <- events |>
  filter(evid == 1) |>
  inner_join(ss_windows |> select(cohort, start_ss, end_ss), by = "cohort") |>
  filter(time == start_ss) |>
  select(id, time, amt, cohort)

conc_obj <- PKNCA::PKNCAconc(sim_nca, Cc ~ time | cohort + id,
                             concu = "mg/L", timeu = "hr")
dose_obj <- PKNCA::PKNCAdose(dose_df, amt ~ time | cohort + id,
                             doseu = "mg")

# Per-cohort intervals (start, end vary by cohort because tau differs)
intervals <- ss_windows |>
  mutate(start = start_ss, end = end_ss,
         cmax = TRUE, tmax = TRUE, cmin = TRUE,
         auclast = TRUE, cav = TRUE) |>
  select(start, end, cmax, tmax, cmin, auclast, cav)

nca_data <- PKNCA::PKNCAdata(conc_obj, dose_obj, intervals = as.data.frame(intervals))
nca_res  <- PKNCA::pk.nca(nca_data)
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=264, end=288: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
#> Warning in .f(data_conc = .l[[1L]][[i]], data_dose = .l[[2L]][[i]],
#> data_intervals = .l[[3L]][[i]], : Error with interval start=132, end=144: No
#> data for interval
nca_summary <- summary(nca_res)
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for auclast
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmin
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for tmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cav
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for auclast
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmin
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for tmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cav
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for auclast
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmin
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for tmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cav
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for auclast
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cmin
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for tmax
#> Warning in summarize_PKNCAresults_parameter(data = current_data, subject_col =
#> subject_col, : Some subjects may have more than one result for cav
knitr::kable(nca_summary,
             caption = "Simulated steady-state NCA parameters by Grimsley 1999 Table 5 creatinine cohort.")
Simulated steady-state NCA parameters by Grimsley 1999 Table 5 creatinine cohort.
Interval Start Interval End cohort N AUClast (hr*mg/L) Cmax (mg/L) Cmin (mg/L) Tmax (hr) Cav (mg/L)
264 288 creat_120_q12 60 529 [23.2], n=120 34.8 [15.5], n=120 12.6 [39.3], n=120 1.00 [1.00, 1.00], n=120 22.0 [23.2], n=120
132 144 creat_20_q12 60 87.0 [19.7], n=120 21.2 [15.2], n=120 1.06 [82.0], n=120 1.00 [1.00, 1.00], n=120 7.25 [19.7], n=120
132 144 creat_45_q12 60 188 [22.1], n=120 28.4 [15.2], n=120 7.13 [44.8], n=120 1.00 [1.00, 1.00], n=120 15.7 [22.1], n=120
264 288 creat_80_q12 60 323 [23.3], n=120 27.3 [16.4], n=120 5.09 [52.3], n=120 1.00 [1.00, 1.00], n=120 13.5 [23.3], n=120

Comparison against published target ranges

Grimsley 1999 designed Table 5 by simulating expected steady-state concentrations and selecting doses that produced troughs of 5-12 mg/L and a 1-hour-post-dose peak of 20-30 mg/L. The packaged model’s typical-value steady-state Cmax and Cmin for each cohort are compared below against those Table 5 targets.

typ_lookup <- sim_typical |>
  inner_join(ss_windows |> select(cohort, start_ss, end_ss), by = "cohort") |>
  filter(time >= start_ss, time <= end_ss) |>
  group_by(cohort) |>
  summarise(
    Cmin_simulated_mg_L = round(min(Cc, na.rm = TRUE), 2),
    Cmax_simulated_mg_L = round(max(Cc, na.rm = TRUE), 2),
    .groups = "drop"
  )

published <- tibble::tribble(
  ~cohort,            ~Table5_dose_mg_kg, ~Table5_interval_h, ~Target_trough_5_12, ~Target_peak_20_30,
  "creat_20_q12",     "20 mg/kg",         "8 h",              "yes",               "yes",
  "creat_45_q12",     "20 mg/kg",         "12 h",             "yes",               "yes",
  "creat_80_q12",     "15 mg/kg",         "24 h",             "yes",               "yes",
  "creat_120_q12",    "15 mg/kg",         "24 h",             "yes (with monitoring)", "yes (with monitoring)"
)

comparison <- typ_lookup |>
  left_join(published, by = "cohort")

knitr::kable(comparison,
             caption = "Simulated typical-value steady-state Cmin / Cmax (this vignette's regimen of 15 mg/kg, q12h for CREAT 20 and 45; q24h for CREAT 80 and 120) alongside the Grimsley 1999 Table 5 nomogram entry for each creatinine band.")
Simulated typical-value steady-state Cmin / Cmax (this vignette’s regimen of 15 mg/kg, q12h for CREAT 20 and 45; q24h for CREAT 80 and 120) alongside the Grimsley 1999 Table 5 nomogram entry for each creatinine band.
cohort Cmin_simulated_mg_L Cmax_simulated_mg_L Table5_dose_mg_kg Table5_interval_h Target_trough_5_12 Target_peak_20_30
creat_120_q12 12.07 33.48 15 mg/kg 24 h yes (with monitoring) yes (with monitoring)
creat_20_q12 1.10 20.53 20 mg/kg 8 h yes yes
creat_45_q12 7.60 27.90 20 mg/kg 12 h yes yes
creat_80_q12 5.89 27.20 15 mg/kg 24 h yes yes

Assumptions and deviations

  • Direct coefficient form for CL and V. Grimsley 1999 publishes the structural model as CL = 3.56 * WT / CREAT and V = 0.669 * WT with no separately estimated covariate exponents. The packaged ini() retains the published coefficients (3.56 and 0.669) verbatim, and model() applies WT and CREAT linearly to reproduce Table 4. Encoding this with explicit fixed() exponents (e_wt_cl = fixed(1), e_creat_cl = fixed(-1), e_wt_vc = fixed(1)) would add machinery the paper never estimates; the literal-equation form is faithful to the source.
  • Power-vs-1/CREAT for clearance. Grimsley 1999 Table 3 compared a power-law CL = theta1 * creatinine^theta2 form against the simpler CL = theta1 / creatinine form and found the simpler form had a delta-OFV of -4.9 versus the estimated-exponent model. The paper retained the simpler form on grounds of parsimony; the packaged model follows that choice.
  • No PCA / GA / PNA / IV-feeding effect. Postconceptual age, gestational age, postnatal age, IV nutrition, dopamine, sex, Apgar score, cardiac status, infection status, and ventilation status were all screened (Grimsley 1999 Results) and not retained in the final model – the paper documents that some achieved borderline significance (IV feeding +21% CL; GA < 35 weeks +27% CL) but were judged confounded or spurious and omitted. The packaged covariatesDataExcluded list preserves the provenance of every screened-but-rejected covariate so downstream users can see what was tested.
  • 1-cmt vs 2-cmt choice. Grimsley 1999 Results note that the 2-compartment model gave a lower OFV than the 1-compartment model (delta = -56.5) under the basic structural model, but the full- covariate 1-compartment model recovered most of the fit (delta = +32.2 vs full 2-cmt) with no apparent advantage of the 2-compartment form on residual plots. The authors chose the 1-compartment model for the dosing nomogram, and the packaged model follows that choice. Downstream users who specifically need to characterise the distribution phase (e.g., for peak modelling during the infusion) should be aware that this is a 1-compartment simplification.
  • Outlier exclusion. One patient with rapidly resolving acute renal injury (serum creatinine 459 -> 316 umol/L over 3 days) was excluded from the development dataset because the rapid covariate change compromised the analysis. Downstream users should treat CREAT as a slowly-varying covariate within the model’s domain of applicability; applying the model when serum creatinine is changing rapidly will give predictions that the authors explicitly judged unreliable.
  • NONMEM Version IV. The model was fit with NONMEM Version IV. The point estimates Table 4 reports were accepted without remark in the paper (no minimization warnings noted), so the packaged values are treated as standard final-model estimates.
  • 67% interval interpretation. Grimsley 1999 Figure 3 labels the ribbon “67% confidence intervals”. In the context of a typical population profile from a routine TDM analysis, this is interpreted as the 16.5-83.5 percentile range of the inter-individual distribution at each time point (a one-SD spread) rather than a confidence interval on the typical-value parameter. The vignette’s Figure 3 replication uses the inter-individual percentile interpretation.
  • Race / ethnicity. Grimsley 1999 enrolled patients at a single-site UK NICU and did not report race or ethnicity. The model does not include race as a covariate; the population metadata records the cohort as “Not reported (single-center cohort at Yorkhill NHS Trust, Glasgow)”.