Bioequivalence evaluation of two preparations containing the highly variable compound selegiline (L-deprenyl)

Selegiline, used in the treatment of Parkinson's disease, inhibits the intracerebral degradation of dopamine and the uptake of catecholamines. Due to a high volume of distribution and also a high rate of biotransformation the concentrations of selegiline in plasma are rather low. In addition, there are indications that selegiline binds to erythrocytes. An open, randomized, 2-way cross-over study was performed in 24 healthy male volunteers to determine bioavailability and pharmacokinetic parameters of 2 oral selegiline preparations after single dose administration. Statistical tests were applied to the pharmacokinetic parameters AUCinf, AUC0-8, AUCz, Cmax and tmax. The terminal half-lives t1/2 for selegiline with geometric means of 1.69 h (n = 22) and 1.76 h (n = 21) for treatments A and B and for N-desmethyl-selegiline with geometric means of 1.98 h and 1.96 h for treatments A and B agreed very well. AUCinf of selegiline could be compared between treatments for 14 subjects only. The geometric mean ratio was 97.80% with a 90% confidence interval that ranged from 79.58%-120.17% and thus exceeded the (80%, 125%) range by a very small margin. After correction for the actual dose contained in each of the 2 preparations the geometric mean ratio was calculated to 98.39% with a 90% confidence interval that ranged from 80.06%-120.90% and thus was fully contained within the (80%, 125%) acceptance range. Treatments also agreed very well with respect to AUCinf of N-desmethyl-selegiline, the active metabolite of selegiline, with a geometric mean ratio of 96.14% with a 90% confidence interval that ranged from 92.41%-100.01% so that bioequivalence of the 2 treatments could be shown very clearly with respect to this metabolite. The AUC of N-desmethyl-selegiline in serum is about 6-fold higher than that of the parent drug. It is assessed with low variability. Thus, it is reasonable to base the judgement for or against bioequivalence primarily on the data obtained for the metabolite although "a larger acceptance range may be acceptable if inevitable and clinically acceptable" for the parent compound selegiline which certainly can be classified as a "highly variable compound".