Interpolating concentration at the the start of an interval for a multiple doses study

[Azenox]

Hi everyone

I'm doing a NCA for a MAD study using both Winnonlin and PKNCA

One of the subjects is missing a concentration at the beginning of the last interval at steady state (predose), Winnonlin estimates a concentration at the start of the interval (time of dosing) and computes the parameters accordingly

PKNCA request a concentration at the start of the interval for AUC ( Requesting an AUC range starting (0) before the first measurement (1) is not allowed ), in this case I have tried to use the imputation function, and calculate the auc.int instead:

df <- data.frame(time=c(312, 313, 313.5, 314, 314.5, 315, 316, 318, 320, 322, 326, 336),
conc=c(NA, 9.69, 10.2, 10, 10.1, 10.1, 10.6, 10.9, 9.92, 8.22, 7.73, 6.39),
subject=1)

conc_obj <- PKNCAconc(as.data.frame(df), conc ~ time)

intervals <- data.frame(start = 312, end = 336,
aucinf.obs=TRUE,
half.life = TRUE,
lambda.z = TRUE,
auclast=TRUE,
aucint.inf.obs =TRUE,
aucint.all =TRUE,
aucint.last =TRUE,
impute = "start_cmin, start_conc0"
)

#Using PKNCA package
PKNCA.options(auc.method = "lin up/log down")
data_obj <- PKNCAdata(conc_obj, intervals = intervals, impute="impute")
results_obj <- pk.nca(data_obj)
results <- as.data.frame(results_obj)

I don't get the same results as winnonlin naturally, I tried the PKNCA::interpolate.conc function to calculate a concentration at 312h, it either returns 0, or if I include the concentration immediately before (at 290.5h) I have an estimate that is slightly higher than what I would expect, and again the AUC parameters don't match those from winnonlin

For the record with Winnonlin I get auc.inf = 552.4472 and auc.last = 201.1562 for this subject

Any clue on the best way to proceed to get the same results without removing the interval between the dose and first concentration?

Thank you

[Azenox]

Well apparenly it was as simple as Wiinonlin using Cmin for first concentration

Is there a way to automate the pk.calc.c0.method.cmin() function in PKNCA, so the interpolation is only done when there is a missing data at the beginning of the interval?