title: Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects.
abstract: 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.
authors.affiliation: Department of Exploratory Medicine, Merck KGaA, D-64293 Darmstadt, Germany. sonja.kroesser@merckgroup.com
authors.forename: Sonja
authors.initials: S
authors.lastname: Krösser
authors.forename: Anne
authors.initials: A
authors.lastname: Marquet
authors.forename: Dieter
authors.initials: D
authors.lastname: Gallemann
authors.forename: Peter
authors.initials: P
authors.lastname: Wolna
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fauchoux
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Johne
mesh_terms: D000328:Adult; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001596:Benzylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D000978:Antiparkinson Agents; D001596:Benzylamines; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C092797:safinamide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000409:Alanine; D007654:Ketoconazole