Bioequivalence and Bioavailability Forum

Dear all,

First, I would like to compliment HS and all contributors with the BEBAC site and forum. It has been and is an outstanding source of information with clear explanations and guidance on BE/BA. It has given me a thorough insight and great knowledge. Although this is my first post, I have been following the site and forum for the past two years, and now am feeling the need to ask for your wisdom on a specific issue regarding AUC_(0-t).

We, as a sponsor, have performed a BE study (N = 16, sampling up to and including t=72 h) in which we have established BE. Because we had major issues in the past with this CRO, specifically on the NCA PK and statistical analyses part, I also conducted all analyses. I used bear for R for these analyses, and double-checked them with SAS, SPSS (SPSS code available if anyone would be interested in how to analyze BE studies with SPSS) and PKSolver (add-in for M$ Excel). All results perfectly match.

In comparison to the analysis by the CRO (the CRO uses WinNonlin and SAS), we have found a small difference in AUC_(0-t), due to the following. One subject showed BLQ values for both T and R products at t=72h (although plasma concentrations for this subject are all on the low side, I cannot find any grounds to qualify him/her as an outlier). According to the protocol, BLQ values should be set to zero (indeed, from a mathematical perspective it would be much nicer to log-linearly extrapolate to t=72 h by using lambda z). The CRO omitted t=72 h values for this subject and calculated AUC_(0-48) for this subject (in fact, according to the CRO, WinNonlin treated the data as such). I kept the 72 h time point in, set it to zero and calculated AUC_(0-72) (i.e. an underestimation of “real” AUC_(0-72)). In my opinion, as the samples at t=72 h were actually drawn and concentrations were not zero but BLQ (i.e. “measurable” but not “quantifiable”, if you get my point), I would opt to keep the values at t=72 h in for this subject (also to have a straight comparison from a statistical perspective). Obviously, the mean (arithmetic, geometric) AUC_(0-t) is higher for both T and R in my calculation.

Indeed, the definition of AUC_(0-t) (i.e. “area under the plasma concentration curve from administration to last observed concentration at t”) can be explained in different ways, but I truly think that this time point has to be kept in the analysis. In the end, difference in PE and CV is very small, but still…

CRO method (omit t=72 h for subject x):
GMR PE = 92.40%
CV = 13.99%

My method (include t=72 h for subject x, set BLQ to zero):
GMR PE = 92.48%
CV = 14.01%

What is your opinion on this issue? Would you omit or include t=72 for subject x in the AUC_(0-t) calculation?

Many thanks in advance!

Best regards,

Oiinkie