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Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects
Author(s) -
Krösser Sonja,
Marquet Anne,
Gallemann Dieter,
Wolna Peter,
Fauchoux Nicolas,
Hermann Robert,
Johne Andreas
Publication year - 2012
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1822
Subject(s) - ketoconazole , pharmacokinetics , pharmacology , cyp3a4 , metabolite , active metabolite , drug interaction , in vivo , medicine , chemistry , cytochrome p450 , endocrinology , metabolism , biology , antifungal , microbiology and biotechnology , dermatology
The purpose of this mechanistic drug interaction study was to investigate the effects of ketoconazole on the pharmacokinetics of safinamide. Ketoconazole was applied as a potent prototypic inhibitor of cytochrome CYP3A4, to determine the role of CYP3A4 in the metabolic clearance of safinamide. In an open‐label, randomized, two‐period, two‐sequence cross‐over study, 14 healthy adult subjects (7 males/7 females) received two single doses of 100 mg safinamide: alone and on top of multiple doses of ketoconazole (200 mg b.i.d.) given over 6 days. Serial blood samples were collected over 240 h post dose to quantify safinamide parent drug and metabolite concentrations for pharmacokinetic evaluation. Safinamide exposure was essentially unchanged when administered with and without ketoconazole: C max and AUC 0‐∞ point estimates (90% CIs) for the treatment comparison were 106.6 (101.0; 112.4) and 112.9 (109.8; 116.03), respectively. Similarly, ketoconazole did not influence the formation and clearance of safinamide metabolites to a clinically relevant extent. Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo . Therefore, safinamide can be administered together with potent CYP3A4 inhibitors without any requirement for dose adjustment. Copyright © 2012 John Wiley & Sons, Ltd.