Analysis of pooled plasma samples as a predictor for proving bioequivalence of drugs with a long elimination half-life. The example of phenprocoumon.

The results of pooled plasma analysis in a bioequivalence trial provide information comparable with that of the mean concentration vs. time curves for each formulation. Although it seems feasible that pool plasma analysis will have similar or even greater advantages in cases of bioequivalence trials with a parallel-group design, no such data has been published in the literature probably due to the limited number of such trials. The present study was designed with the aim to investigate the prediction value of pool plasma analysis in a bioequivalence trial with phenprocoumon (CAS 435-972). The study was performed as a monocentric, randomized, open clinical trial in two parallel groups of healthy male volunteers (31 per group), all of which received a single oral dose of 3 mg phenprocoumon. Serial blood samples were drawn for the pharmacokinetic analysis pre-dose, and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 12, 24, 48, 96, 144, 192, and 240 h after drug administration. Pool plasma was prepared for each sampling point and each formulation. Drug concentrations were measured by means of an HPLC method. A comparison between the pool plasma results and the results of individual analysis revealed a very good correspondence regarding the parameters AUC, Cmax and t(max). The present trial demonstrates that the method of time-wise pooling provides reliable information not only in cross-over trials but also in trials with parallel groups of volunteers.