Terminal BLQ Values and AUCinf Estimation

[dabou003]

In a DDI study that included 27 subjects, our analyte was assessed with and without a co-administered drug for 0-120 h. The analyte was not detectable in any subject after 24 h and was detected in only 6–8 subjects at the 24-h time point and in 20 subjects at 12 h. All concentrations after 24 h through 120 h were BLOQ.

I am trying to fit the data to assess the GMR for AUCinf, but I am challenged by the fact that, for most subjects, the percentage of extrapolated AUC exceeds 20%. Can the algorithm in PKNCA impute values based on the observed terminal phase?

Please note that I have tried the imputation methods outlined in this paper. However, the methods described require at least some subjects to have observed values at these time points (24-120) to impute values for the other subjects.

The elimination half-life of our analyte typically ranges from 10 to 20 hours.

[billdenney]

Methods to extrapolate beyond the observed data are beyond the methods used for NCA, typically. And, any extrapolation of concentrations beyond the observed data would be atypical. You can try the Tobit half life method (https://humanpred.github.io/pknca/articles/v06-half-life-calculation-tobit.html), but it won't likely change things meaningfully.

And, any extrapolation method used would not change the fact that the extrapolation is greater than 20% (since the points used would be extrapolated). There is an interp.extrap.conc which will use the half life to extrapolate additional concentrations for you. Since it is using the half life you already have, it will give a very similar AUCinf.

What I would recommend doing (and what is typically done) is to use either AUClast or AUCall as an alternate comparison.

[dabou003]

Thank you so much for your prompt response and very clear clarification.