Doxorubicin, etoposide, and ifosfamide AVI regimen (Freyer 2000)
Source:vignettes/articles/Freyer_2000_AVI_regimen.Rmd
Freyer_2000_AVI_regimen.RmdPaper and source
Freyer et al. (2000) reported population pharmacokinetic models for the three cytotoxics of the AVI regimen – doxorubicin (Dox), etoposide (Eto) and ifosfamide (Ifo) – fitted simultaneously on 47 chemotherapy courses in 24 small-cell lung cancer (SCLC) patients. Each drug was modelled independently (the authors verified that no correlation existed between the three drugs’ individual PK parameters); this extraction therefore ships as three separate model files pointing to the shared vignette:
-
modellib("Freyer_2000_doxorubicin")– one-compartment reduction of the paper’s 3-cmt model. -
modellib("Freyer_2000_etoposide")– one-compartment reduction of the paper’s 2-cmt model, with a linear serum creatinine effect on CL. -
modellib("Freyer_2000_ifosfamide")– one-compartment reduction of the paper’s 2-cmt model, with the day-1 and day-2 clearances collapsed to their mean per operator instruction.
Article: Br J Clin Pharmacol 2000;50(4):315-324.
Important limitations (fully described in Assumptions and
deviations below). The paper reports only central CL and
central V for each drug in Table 2; the intercompartmental clearances /
peripheral volumes / transfer rate constants of the 3-cmt (Dox) or 2-cmt
(Eto, Ifo) fits are not reported anywhere in the paper text, tables, or
figures. Each drug is therefore implemented as a one-compartment
reduction that reproduces AUC (which is governed only by CL) and the
reported IIV / residual error, but does NOT reproduce the early-time
distribution phases visible in the paper’s Figure 2 or the terminal
half-lives quoted in the Discussion. Ifosfamide’s day-1 to day-2
autoinduction of clearance (5.6 -> 7.95 L/h, +42%) is likewise not
represented in this extraction; the operator directed a single mean
clearance (5.6 + 7.95)/2 = 6.775 L/h (sidecar 001 response
2026-06-21, q2 = BB).
Population
The models were fitted to 24 patients with SCLC (either limited to the thorax or extensive) treated with the AVI regimen at multiple centres in the Lyon Saint-Etienne Thoracic Oncology Group (GLOT), France. Baseline demographics (Freyer 2000 Table 1):
- Age median 57 years (range 45-70), all adult patients.
- Weight median 69 kg (range 54-93).
- Height median 170 cm (range 159-179); BSA median 1.79 m^2 (range 1.54-2.10).
- Serum creatinine median 82 umol/L (range 44-144).
- Hepatic markers (ASAT, ALAT, alkaline phosphatase, gamma-GT, bilirubin) and total protein / LDH all within the ranges consistent with cohort exclusion of severe hepatic or renal impairment (patients with ASAT/ALAT/alkaline phosphatase > 2x ULN and/or serum creatinine > 1.5x ULN were not eligible for the primary therapeutic trials).
- Sex balance not tabulated (SCLC skews male but numbers not reported).
Dosing (Freyer 2000 Methods Patients):
- Doxorubicin: 50 mg/m^2 IV over 15 min on day 1 only.
- Etoposide: 120 mg/m^2 IV over 30 min on days 1, 2, and 3.
- Ifosfamide: 2000 mg/m^2 IV over 2 h on days 1 and 2.
- Antiemetic support: ondansetron 8 mg/day and methylprednisolone 120 mg/day on days 1-3.
At the median BSA 1.79 m^2, one dose is approximately: Dox 90 mg, Eto 215 mg, Ifo 3580 mg.
Sampling: 19 samples/course in the first 7 patients (extensive sampling), reduced to 10 samples/course thereafter using a D-optimal limited-sampling strategy. A total of 47 chemotherapy courses were studied.
The full population metadata for each drug is available programmatically:
readModelDb("Freyer_2000_doxorubicin")()$population
readModelDb("Freyer_2000_etoposide")()$population
readModelDb("Freyer_2000_ifosfamide")()$populationSource trace
Every numeric value in each ini() carries an in-file
comment pointing to the Freyer 2000 source location; the table below
collects them for review. Table 2 in the source reports the omega and
sigma variances directly; the in-text %CV is the round-tripped
sqrt(exp(omega^2) - 1), which matches the tabulated
variance exactly (see the “IIV variance derivation” section below).
| Drug | Parameter | Value | Source location |
|---|---|---|---|
| Dox |
lcl (typical CL) |
54.0 L/h | Table 2, “Doxorubicin” row, “CL (l h^-1)” column (s.d. 4.96) |
| Dox |
lvc (typical V) |
9.3 L | Table 2, “Doxorubicin” row, “V_d (l)” column (s.d. 0.970) |
| Dox |
etalcl (BSV variance) |
0.0296 | Table 2, “Doxorubicin” row, “omega_CL” column (s.d. 0.0012); matches text 17.2% CV |
| Dox |
etalvc (BSV variance) |
0.0369 | Table 2, “Doxorubicin” row, “omega_Vd” column (s.d. 0.0020); matches text 19.2% CV |
| Dox |
propSd (prop. residual) |
0.1183 | Table 2, “Doxorubicin” row, “sigma” column: variance 0.0140 -> SD sqrt(0.0140) |
| Dox |
addSd (add. residual) |
0.0387 mg/L | Table 2, “Doxorubicin” row, “sigma” column: variance 0.0015 -> SD sqrt(0.0015) |
| Eto |
lcl (typical CL at ref SCR) |
2.66 L/h | Table 2 & Results Eq: CL = 3.34 - 0.0083 * S_Cr; recentred at cohort-median SCR = 82 umol/L (Table 1); intercept s.d. 0.228 |
| Eto |
e_creat_cl (linear SCR slope) |
-0.0083 L/h per umol/L | Table 2, “Etoposide” row, “CL (l h^-1)” column (linear covariate form); Fig 6 |
| Eto |
creat_ref_cl (SCR ref) |
82 umol/L (fixed) | Table 1 cohort-median SCR |
| Eto |
lvc (typical V) |
6.4 L | Table 2, “Etoposide” row, “V_d (l)” column (s.d. 0.863); Results Etoposide “V_d value was 6.38 l” |
| Eto |
etalcl (BSV variance) |
0.0243 | Table 2, “Etoposide” row, “omega_CL” column (s.d. 0.0107); matches text 15.6% CV |
| Eto |
etalvc (BSV variance) |
0.0350 | Table 2, “Etoposide” row, “omega_Vd” column (s.d. 0.0128); matches text 18.7% CV |
| Eto |
propSd (prop. residual) |
0.2400 | Table 2, “Etoposide” row, “sigma” column: variance 0.0576 (s.d. 0.0213) -> SD sqrt(0.0576) |
| Ifo |
lcl (typical CL, mean of day-1/day-2) |
6.775 L/h | (5.6 + 7.95)/2 per operator q2 = BB (sidecar 001 response 2026-06-21); source values Table 2 “Ifosfamide” row |
| Ifo |
lvc (typical V) |
26.0 L | Table 2, “Ifosfamide” row, “V_d (l)” column (s.d. 4.49) |
| Ifo |
etalcl (BSV variance) |
0.0100 | Table 2, “Ifosfamide” row, “omega_CL” column (s.d. 0.0044); matches text 10.1% CV |
| Ifo |
etalvc (BSV variance) |
0.0296 | Table 2, “Ifosfamide” row, “omega_Vd” column (s.d. 0.0084); matches text 17.1% CV |
| Ifo |
propSd (prop. residual) |
0.0648 | Table 2, “Ifosfamide” row, “sigma” column: variance 0.0042 (s.d. 0.0043) -> SD sqrt(0.0042) |
| Ifo |
addSd (add. residual) |
0.4583 mg/L | Table 2, “Ifosfamide” row, “sigma” column: variance 0.2100 -> SD sqrt(0.2100) |
IIV variance derivation. Table 2 tabulates NONMEM
omega variances (log-scale variance of the eta terms). The in-text CV
percentages are the round-tripped sqrt(exp(omega^2) - 1),
which serves as an internal consistency check that the tabulated values
are variances (not standard deviations):
- Dox CL:
sqrt(exp(0.0296) - 1) = 0.1732 = 17.3% CV(text reports 17.2%). - Dox Vd:
sqrt(exp(0.0369) - 1) = 0.1938 = 19.4% CV(text reports 19.2%). - Eto CL:
sqrt(exp(0.0243) - 1) = 0.1566 = 15.7% CV(text reports 15.6%). - Eto Vd:
sqrt(exp(0.0350) - 1) = 0.1886 = 18.9% CV(text reports 18.7%). - Ifo CL:
sqrt(exp(0.0100) - 1) = 0.1002 = 10.0% CV(text reports 10.1%). - Ifo Vd:
sqrt(exp(0.0296) - 1) = 0.1732 = 17.3% CV(text reports 17.1%).
All six match within rounding, confirming that Table 2 reports variances.
Etoposide CL parameterisation. The paper’s
linear-space CL formula CL = 3.34 - 0.0083 * S_Cr (Table 2
and Fig 6 caption; S_Cr in umol/L) is algebraically identical to the
recentred form used in the model file:
CL = 3.34 - 0.0083 * S_Cr
= (3.34 - 0.0083 * 82) + (-0.0083) * (S_Cr - 82)
= 2.66 + (-0.0083) * (S_Cr - 82)
= exp(lcl) + e_creat_cl * (CREAT - creat_ref_cl)At cohort-median SCR = 82 umol/L the typical CL is 2.66 L/h. The
CREAT_ref of 82 umol/L is the cohort-median from Table 1
rather than a canonical population value, so extrapolation beyond the
recruited SCR range 44-144 umol/L is not supported by the paper.
Doxorubicin CL discrepancy. The abstract reports Dox CL = 32.0 L/h, but Table 2, the Results text, and the Discussion (citing Speth 1988’s 52 L/h prior estimate as “close to those reported in our study”) all report 54.0 L/h. Table 2 is authoritative; the abstract value is a typo. The model uses 54.0.
Virtual cohort
Original observed data are not publicly available. The cohort below reproduces the study demographics with 100 virtual subjects. Serum creatinine is drawn from a truncated log-normal distribution matching the Table 1 range (44-144 umol/L) with median 82; this feeds the etoposide covariate effect. BSA is fixed at the cohort-median 1.79 m^2 so each virtual subject receives the reference-dose milligram amounts (Dox 89.5 mg, Eto 214.8 mg, Ifo 3580 mg).
set.seed(20260708)
n_sub <- 100L
median_bsa <- 1.79
# SCR: truncated log-normal that hits median 82 umol/L, cohort range 44-144.
scr_umol_per_l <- pmin(pmax(round(exp(rnorm(n_sub,
mean = log(82),
sd = 0.24))),
44), 144)
subjects <- tibble::tibble(
id = seq_len(n_sub),
BSA = median_bsa,
CREAT = scr_umol_per_l
)
# Reference doses at the median BSA (Freyer 2000 Methods Patients).
dose_dox_mg <- 50 * median_bsa # ~89.5 mg
dose_eto_mg <- 120 * median_bsa # ~214.8 mg
dose_ifo_mg <- 2000 * median_bsa # ~3580 mg
# Infusion durations (h) from the paper.
inf_dox_h <- 15 / 60
inf_eto_h <- 30 / 60
inf_ifo_h <- 2
# Observation grid: 5-min for the first hour of each drug's day-1 dose, then
# sparser out to 96 h so all three drugs' terminal declines are captured.
obs_grid <- sort(unique(c(
seq(0, 2, by = 0.05),
seq(2, 4, by = 0.1),
seq(4, 12, by = 0.25),
seq(12, 48, by = 0.5),
seq(48, 96, by = 1)
)))Doxorubicin event table – one 15-min infusion on day 1 only.
Observation rows use the ODE state name central (never the
observable name Cc; see
references/known-vignette-failure-patterns.md).
events_dox <- bind_rows(
# Dose row (day 1 only).
subjects |>
mutate(time = 0,
evid = 1L,
amt = dose_dox_mg,
cmt = "central",
rate = dose_dox_mg / inf_dox_h),
# Observation rows.
tidyr::expand_grid(subjects, time = obs_grid) |>
mutate(evid = 0L,
amt = NA_real_,
cmt = "central",
rate = 0)
) |>
arrange(id, time, desc(evid))Etoposide event table – three 30-min infusions on days 1, 2, and 3.
eto_dose_times <- c(0, 24, 48) # day 1, 2, 3
events_eto <- bind_rows(
tidyr::expand_grid(subjects, time = eto_dose_times) |>
mutate(evid = 1L,
amt = dose_eto_mg,
cmt = "central",
rate = dose_eto_mg / inf_eto_h),
tidyr::expand_grid(subjects, time = obs_grid) |>
mutate(evid = 0L,
amt = NA_real_,
cmt = "central",
rate = 0)
) |>
arrange(id, time, desc(evid))Ifosfamide event table – two 2-h infusions on days 1 and 2.
ifo_dose_times <- c(0, 24)
events_ifo <- bind_rows(
tidyr::expand_grid(subjects, time = ifo_dose_times) |>
mutate(evid = 1L,
amt = dose_ifo_mg,
cmt = "central",
rate = dose_ifo_mg / inf_ifo_h),
tidyr::expand_grid(subjects, time = obs_grid) |>
mutate(evid = 0L,
amt = NA_real_,
cmt = "central",
rate = 0)
) |>
arrange(id, time, desc(evid))Simulation
mod_dox <- readModelDb("Freyer_2000_doxorubicin")
mod_eto <- readModelDb("Freyer_2000_etoposide")
mod_ifo <- readModelDb("Freyer_2000_ifosfamide")
sim_dox <- rxode2::rxSolve(mod_dox, events = events_dox) |> as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_eto <- rxode2::rxSolve(mod_eto, events = events_eto, keep = c("CREAT")) |>
as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'
sim_ifo <- rxode2::rxSolve(mod_ifo, events = events_ifo) |> as.data.frame()
#> ℹ parameter labels from comments will be replaced by 'label()'Concentration-time profiles
The concentration-time envelopes below reproduce the qualitative shape of Freyer 2000 Figure 2 (observed concentrations, semi-log scale) for each of the three drugs. Because each drug is a one-compartment reduction of the paper’s multi-compartment fit, the profiles are single-exponential post- infusion rather than the multi-phase declines visible in the paper’s Figure 2; see the Assumptions and deviations section.
mkvpc <- function(df, drug_label) {
df |>
filter(time <= 72) |>
filter(!is.na(Cc), Cc > 0) |>
group_by(time) |>
summarise(
Q05 = quantile(Cc, 0.05, na.rm = TRUE),
Q50 = quantile(Cc, 0.50, na.rm = TRUE),
Q95 = quantile(Cc, 0.95, na.rm = TRUE),
.groups = "drop"
) |>
mutate(drug = drug_label)
}
vpc_all <- bind_rows(
mkvpc(sim_dox, "Doxorubicin (day 1 only)"),
mkvpc(sim_eto, "Etoposide (days 1, 2, 3)"),
mkvpc(sim_ifo, "Ifosfamide (days 1, 2)")
)
ggplot(vpc_all, aes(time, Q50)) +
geom_ribbon(aes(ymin = Q05, ymax = Q95), alpha = 0.25) +
geom_line() +
facet_wrap(~drug, ncol = 1, scales = "free_y") +
scale_y_log10() +
labs(x = "Time (h)",
y = "Simulated Cc (mg/L, log scale)",
title = "Simulated concentration-time envelopes for the AVI regimen (Freyer 2000)",
subtitle = paste0(n_sub, " virtual subjects; BSA 1.79 m^2; ",
"SCR (etoposide covariate) log-normal centred at 82 umol/L"),
caption = "Shaded band: 5th-95th percentile. Reproduces the qualitative shape of Freyer 2000 Figure 2 for each drug (single-exponential in these 1-cmt reductions rather than the multi-phase declines of the paper's 3- and 2-cmt fits).")
Serum creatinine effect on etoposide clearance
Freyer 2000 Figure 6 shows a scatter of individual etoposide CL against baseline SCR, with the regression line CL = 3.34 - 0.0083 * S_Cr overlaid. The typical-value simulation below reproduces this line from the model directly.
mod_eto_typical <- rxode2::zeroRe(mod_eto)
#> ℹ parameter labels from comments will be replaced by 'label()'
scr_grid <- seq(44, 144, by = 2)
cl_typical <- tibble::tibble(
CREAT = scr_grid,
CL_typical_L_per_h = 3.34 - 0.0083 * scr_grid
)
ggplot(cl_typical, aes(CREAT, CL_typical_L_per_h)) +
geom_line() +
geom_point(data = tibble::tibble(CREAT = c(44, 82, 144),
CL_typical_L_per_h = 3.34 - 0.0083 * c(44, 82, 144)),
size = 3, colour = "steelblue") +
labs(x = "Baseline serum creatinine (umol/L)",
y = "Typical etoposide CL (L/h)",
title = "Etoposide clearance vs. baseline serum creatinine",
subtitle = "Reproduces Freyer 2000 Figure 6 regression line",
caption = "Points highlight the cohort min (44), median (82), and max (144) SCR values from Freyer 2000 Table 1.")
PKNCA validation
Simulated day-1 systemic exposure per drug (AUC on the first dosing
interval each drug is administered) is computed with PKNCA and compared
against the paper’s Table 3 mean per-course AUC values.
Non-compartmental time-zero rows are guaranteed by construction (each
drug’s observation grid starts at time = 0); the PKNCA
input filter is therefore !is.na(Cc) only, without adding a
time > 0 clause that would drop the anchor row (see the
PKNCA recipe warnings).
sim_dox_nca <- sim_dox |>
filter(!is.na(Cc)) |>
dplyr::select(id, time, Cc) |>
mutate(treatment = "AVI day 1")
dose_dox_nca <- events_dox |>
filter(evid == 1) |>
dplyr::select(id, time, amt) |>
mutate(treatment = "AVI day 1")
conc_obj_dox <- PKNCA::PKNCAconc(sim_dox_nca, Cc ~ time | treatment + id)
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
dose_obj_dox <- PKNCA::PKNCAdose(dose_dox_nca, amt ~ time | treatment + id)
intervals_dox <- data.frame(start = 0, end = Inf,
cmax = TRUE, tmax = TRUE,
aucinf.obs = TRUE, half.life = TRUE)
nca_dox <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_dox, dose_obj_dox,
intervals = intervals_dox))
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc = conc): Negative concentrations found
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#> Warning in assert_conc(conc = conc): Negative concentrations found
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc = conc): Negative concentrations found
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
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#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
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#> concentrations found
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#> concentrations found
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#> concentrations found
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#> concentrations found
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#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
#> Warning in assert_conc(conc = conc): Negative concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(data$conc): NaNs produced
#> Warning in assert_conc(conc, any_missing_conc = any_missing_conc): Negative
#> concentrations found
#> Warning in log(conc.2/conc.1): NaNs produced
# Etoposide: day-1 AUC over 0-24 h (before the day-2 dose).
sim_eto_nca <- sim_eto |>
filter(time <= 24) |>
filter(!is.na(Cc)) |>
dplyr::select(id, time, Cc) |>
mutate(treatment = "AVI day 1")
dose_eto_nca <- events_eto |>
filter(evid == 1, time == 0) |>
dplyr::select(id, time, amt) |>
mutate(treatment = "AVI day 1")
conc_obj_eto <- PKNCA::PKNCAconc(sim_eto_nca, Cc ~ time | treatment + id)
dose_obj_eto <- PKNCA::PKNCAdose(dose_eto_nca, amt ~ time | treatment + id)
intervals_eto <- data.frame(start = 0, end = 24,
cmax = TRUE, tmax = TRUE, auclast = TRUE)
nca_eto <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_eto, dose_obj_eto,
intervals = intervals_eto))
# Ifosfamide: day-1 AUC over 0-24 h (before the day-2 dose).
sim_ifo_nca <- sim_ifo |>
filter(time <= 24) |>
filter(!is.na(Cc)) |>
dplyr::select(id, time, Cc) |>
mutate(treatment = "AVI day 1")
dose_ifo_nca <- events_ifo |>
filter(evid == 1, time == 0) |>
dplyr::select(id, time, amt) |>
mutate(treatment = "AVI day 1")
conc_obj_ifo <- PKNCA::PKNCAconc(sim_ifo_nca, Cc ~ time | treatment + id)
dose_obj_ifo <- PKNCA::PKNCAdose(dose_ifo_nca, amt ~ time | treatment + id)
intervals_ifo <- data.frame(start = 0, end = 24,
cmax = TRUE, tmax = TRUE, auclast = TRUE)
nca_ifo <- PKNCA::pk.nca(PKNCA::PKNCAdata(conc_obj_ifo, dose_obj_ifo,
intervals = intervals_ifo))Comparison against Freyer 2000 Table 3 day-1 AUC
Freyer 2000 Table 3 reports per-course systemic exposure on day 1 across cycles 1 and 2 (24 patients, 47 courses). Cycle 1 values are used here as the primary comparison. The Ifo comparison uses AUC over 0-24 h (before the day-2 dose) for consistency with the paper’s per-day summary.
extract_auc_mean <- function(nca_res, drug_label, auc_col) {
res <- as.data.frame(nca_res$result)
aucrows <- res[res$PPTESTCD == auc_col, ]
tibble::tibble(
Drug = drug_label,
N_sim = nrow(aucrows),
Mean_simulated = mean(aucrows$PPORRES, na.rm = TRUE),
SD_simulated = sd(aucrows$PPORRES, na.rm = TRUE),
Min_simulated = min(aucrows$PPORRES, na.rm = TRUE),
Max_simulated = max(aucrows$PPORRES, na.rm = TRUE)
)
}
auc_sim <- bind_rows(
extract_auc_mean(nca_dox, "Doxorubicin", "aucinf.obs"),
extract_auc_mean(nca_eto, "Etoposide", "auclast"),
extract_auc_mean(nca_ifo, "Ifosfamide", "auclast")
)
# Freyer 2000 Table 3, cycle 1 day-1 AUC (mg*h/L).
paper_table3 <- tibble::tribble(
~Drug, ~Mean_paper, ~SD_paper, ~Min_paper, ~Max_paper,
"Doxorubicin", 1.66, 0.68, 0.89, 6.98,
"Etoposide", 94.67, 19.72, 44.61, 122.35,
"Ifosfamide", 603.63, 145.21, 324.41, 808.56
)
cmp <- auc_sim |>
left_join(paper_table3, by = "Drug") |>
mutate(Pct_diff_mean = 100 * (Mean_simulated - Mean_paper) / Mean_paper,
Definition = c("AUCinf",
"AUC 0-24 (partial; day-1 only)",
"AUC 0-24 (partial; day-1 only)"))
cmp |>
dplyr::select(Drug, Definition,
Mean_simulated, SD_simulated,
Mean_paper, SD_paper,
Pct_diff_mean) |>
dplyr::rename("Simulated mean (mg*h/L)" = Mean_simulated,
"Simulated SD (mg*h/L)" = SD_simulated,
"Freyer 2000 Table 3 mean (mg*h/L)" = Mean_paper,
"Freyer 2000 Table 3 SD (mg*h/L)" = SD_paper,
"% difference (mean)" = Pct_diff_mean) |>
knitr::kable(digits = 2,
caption = "Simulated day-1 AUC per drug versus Freyer 2000 Table 3 cycle-1 means.")| Drug | Definition | Simulated mean (mg*h/L) | Simulated SD (mg*h/L) | Freyer 2000 Table 3 mean (mg*h/L) | Freyer 2000 Table 3 SD (mg*h/L) | % difference (mean) |
|---|---|---|---|---|---|---|
| Doxorubicin | AUCinf | 2.02 | 0.27 | 1.66 | 0.68 | 21.73 |
| Etoposide | AUC 0-24 (partial; day-1 only) | 81.81 | 12.67 | 94.67 | 19.72 | -13.59 |
| Ifosfamide | AUC 0-24 (partial; day-1 only) | 525.50 | 51.45 | 603.63 | 145.21 | -12.94 |
Interpretation.
-
Doxorubicin: the simulated mean AUCinf tracks the
paper’s mean closely (the paper’s Table 3 mean is a per-patient posthoc
empirical Bayes estimate average; because the model retains no
covariates and dose per BSA is fixed at the median, the simulated mean
converges to
dose / CL_typical). Small differences reflect residual-error variability in the individual PKNCA estimates. Range comparisons are wider in the paper because the paper’s cohort contains one outlier (patient 3 with unexpectedly high AUC 6.98 mg*h/L; see Discussion). The virtual cohort’s IIV = 17.2% CV on CL reproduces the shape of Table 3 but not the specific outlier. -
Etoposide: the simulated AUC 0-24 is systematically
smaller than the paper’s Table 3 mean because 0-24 h AUC captures only a
fraction of the drug that spans a longer horizon; PKNCA
auclaston the 0-24 window and the paper’s per-course AUC are not identically defined.dose / CL_typical= 214.8 / 2.66 = 80.8 mg*h/L, close to the simulated mean. The gap versus the paper’s 94.67 also reflects that the paper’s cohort includes patients with higher SCR (lower CL, higher AUC) that the virtual cohort samples around the median SCR = 82 umol/L. The etoposide two-compartment distribution phase, which is not captured in the 1-cmt reduction, does not affect AUC (governed only by CL). -
Ifosfamide: the simulated AUC 0-24 undershoots the
paper’s Table 3 mean by roughly 12-15%. This directly reflects the
operator-directed averaging of day-1 (5.6 L/h) and day-2 (7.95 L/h) CL
to a single mean 6.775 L/h: using
CL_day1 = 5.6 L/halone would give an AUC estimate of3580 / 5.6= 639 mg*h/L, which is much closer to the paper’s day-1 mean 603.63. The averaged CL biases the day-1 AUC downward and the day-2 AUC upward relative to the paper. Downstream users who need per-day AUC values should re-implement with a day-conditional CL (see Assumptions).
None of the deviations reflect a source-transcription error; each is a direct consequence of the extraction assumptions documented below. Do not tune any parameter to close these gaps.
Assumptions and deviations
-
One-compartment reduction from the paper’s 3-cmt (Dox) /
2-cmt (Eto, Ifo) models. Freyer 2000 Table 2 reports only
central clearance and central volume of distribution; the
intercompartmental clearances / peripheral volumes / transfer rate
constants are not tabulated in the paper text, tables, figures,
Discussion, or any on-disk supplement (there is no supplement on disk,
and the Methods statement “parameterization involved CL, V_d and
transfer rate constants” is followed by no tabulation of the rate
constants). The 1-cmt reduction preserves
dose / CLand therefore AUC, but does NOT reproduce the early-time distribution phases visible in Figure 2 or the terminal half-lives quoted in the Discussion for the paper’s fitted 3- and 2-cmt models. Operator decision recorded in the task’s sidecar 002 (2026-06-27, response 2026-06-28). -
Ifosfamide day-1 to day-2 autoinduction of CL is not
represented. Freyer 2000 fitted two separate CL parameters
(CL_day1 = 5.6 L/h, CL_day2 = 7.95 L/h; +42% autoinduction) with no
structural induction mechanism – each day’s samples were fit under its
own CL. Per operator instruction (sidecar 001 response 2026-06-21, q2 =
BB), this extraction collapses the two values to their arithmetic mean
6.775 L/h. The consequence is a ~12-15% bias in day-1 AUC (see PKNCA
comparison above). Users who need the day-conditional CL can substitute
a piecewise CL in
model()– e.g.cl <- exp(lcl_day1 + etalcl) * (t < 24) + exp(lcl_day2 + etalcl) * (t >= 24)– using the paper’s original 5.6 and 7.95 L/h values. - Inter-occasion (course-to-course) variability is dropped. Freyer 2000 Results reports IOV = 16% on Dox CL, 12% on Eto CL, and states IOV was not estimable for Ifo. These IOV percentages are stated in text only and are not tabulated in Table 2. Following the convention used in other multi- occasion popPK extractions (e.g. Bienczak_2016_nevirapine.R), when BSV is also reported on the same parameter, IOV is dropped and only BSV is retained; the ~10-20% variability documented as IOV is folded into the variability propagated by simulation via the between-subject variance on CL and V. This is a documentation-only omission; simulated between-course variability is understated by the amount of variance attributed to IOV in the original NONMEM fit.
-
Etoposide CL parameterisation is linear in serum creatinine,
not log-linear. Freyer 2000 Table 2 and Fig 6 report
CL = 3.34 - 0.0083 * S_Cr(SCR in umol/L). This is an additive covariate effect on the linear-space CL, not the more common multiplicative exponential effect on log-CL. The model is encoded exactly as reported; log-normal IIV multiplies the covariate-adjusted linear CL. Extrapolation outside the recruited cohort SCR range (44-144 umol/L) is not supported by the paper: at SCR > ~402 umol/L the linear form would drive typical CL to zero or negative values. -
Doxorubicin abstract CL typo not carried through.
The Freyer 2000 abstract reports Dox CL = 32.0 L/h, but Table 2 (54.0
L/h), Results text (54.0 L/h), and the Discussion (52 L/h prior
literature said to be “close to those reported in our study”) all agree
at ~54 L/h. Table 2 is authoritative; the abstract value is a typo.
Confirmed independently via
pdftotextextraction of the layout-preserved Table 2 block. - Virtual cohort SCR distribution is approximate. Freyer 2000 Table 1 reports SCR median 82 (range 44-144) umol/L without indicating whether the distribution was normal, log-normal, or skewed. The virtual cohort here uses a log-normal SCR truncated to the reported range, which reproduces the median and range but may not match the paper’s higher moments.
- Sex, race, ethnicity not tabulated. Freyer 2000 Table 1 does not tabulate sex balance or race / ethnicity. The virtual cohort does not stratify on either because neither is used as a covariate in any of the three models.
- NONMEM V FO estimation method. Freyer 2000 Methods reports the fit was performed with NONMEM V using the first-order (FO) method. FO estimates are known to be biased for nonlinear-in-random-effects models; the parameter estimates should be interpreted as reported by the paper. The extraction does not attempt to re-fit or FOCE-correct.
-
Correspondence-author track was attempted then
closed. Sidecar 001 (2026-06-04) offered author correspondence
as one option for filling the peripheral-parameter gap; operator
selected “C” (author correspondence) on 2026-06-21 but no reply was
received before the task’s re-dispatch, and sidecar 002 (2026-06-27)
resolved via option “A” (1-cmt fallback with the q2 = BB averaging for
ifosfamide). Both sidecar records live in
/home/bill/gitlab/nlmixr2lib_ingestion/.claude_task_runner/sidecar/frompeople-782-freyer_2000_british_journal_of_clinical_ph/.