BIOEQUIVALENCE EVALUATION OF 2 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 catecholamine s. Due to a high volume of distribution and also a high rate of biotra nsformation the concentrations of selegiline in plasma are rather low. In addition, there are indications that selegiline binds to erythrocy tes. An open, randomized, 2-way cross-over study was performed in 24 h ealthy male volunteers to determine bioavailability and pharmacokineti c parameters of 2 oral selegiline preparations after single dose admin istration, Statistical tests were applied to the pharmacokinetic param eters AUC(inf), AUC(0-8), AUC(z), C-max and t(max). The terminal half- lives t(1/2) for selegiline with geometric means of 1.69 h (n = 22) an d 1.76 h (n = 21) for treatments A and B and for N-desmethyl-selegilin e with geometric means of 1.98 h and 1.96 h for treatments A and B agr eed very well. AUC(inf) of selegiline could be compared between treatm ents 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 exc eeded the (80%, 125%) range by a very small margin. After correction f or the actual dose contained in each of the 2 preparations the geometr ic 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 wit h respect to AUC(inf) of N-desmethyl-selegiline, the active metabolite of selegiline, with a geometric mean ratio of 96.14% with a 90% confi dence interval that ranged from 92.41% - 100.01% so that bioequivalenc e 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-fol d higher than that of the parent drug. It is assessed with low variabi lity. Thus, it is reasonable to base the judgement for or against bioe quivalence primarily on the data obtained for the metabolite although ''a larger acceptance range may be acceptable if inevitable and clinic ally acceptable'' for the parent compound selegiline which certainly c an be classified as a ''highly variable compound''.