Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men

• Published in: Current medical research and opinion Vol. 23; no. 6; pp. 1415 - 1422
• Main Authors: Krishna, Gopal, Sansone-Parsons, Angela, Kantesaria, Bhavna
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.06.2007; Taylor & Francis; Informa Healthcare
• Subjects: Administration, Oral; Adolescent; Adult; Anticonvulsants - administration & dosage; Anticonvulsants - adverse effects; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - blood; Antifungal Agents - pharmacokinetics; Drug Administration Schedule; Drug interaction; Drug Interactions; Humans; Male; Middle Aged; Pharmacokinetics; Phenytoin; Phenytoin - administration & dosage; Phenytoin - adverse effects; Phenytoin - blood; Phenytoin - pharmacokinetics; Polypharmacy; Posaconazole; Safety; Time Factors; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - blood; Triazoles - pharmacokinetics
• ISSN: 0300-7995; 1473-4877; 1473-4877
• DOI: 10.1185/030079907X187937

ABSTRACT Objective: Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This randomized, open-label, parallel-group, multiple-dose study was conducted in healthy adult volunteers to assess the potential for a drug interaction between phenytoin and the posaconazole tablet formulation. Methods: Subjects were randomly assigned for 10 days to one of the following treatments: posaconazole (200 mg once daily), phenytoin (200 mg once daily), or posacon­azole (200 mg once daily) and phenytoin (200 mg once daily). Blood samples were collected on days 1 and 10 for pharmacokinetic evaluation of posaconazole and pheny­toin concentrations. Results: A total of 36 healthy men enrolled in the study. On day 1, the maximum plasma concentration (Cmax) and area under the concentration–time curve calculated from time 0–24 h post-dose (AUC(0–24)) were unchanged upon co-administration. At steady state (day 10), co-administra­tion of posaconazole with phenytoin resulted in 44% ( p = 0.012) and 52% ( p = 0.007) decreases in posaconazole Cmax and AUC(0–24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin Cmax and AUC(0–24) were not significantly altered upon co-administration of the two agents, 24% increase in Cmax ( p = 0.196) and 25% increase in AUC(0–24) ( p = 0.212) values, although inter-subject variability was observed within this group. Conclusion: Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin levels in some subjects, concomitant use of these agents should be avoided unless the benefit outweighs the risk.