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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.)