Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men.
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 (C(max)) 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 C(max) and AUC(0-24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin C(max) and AUC(0-24) were not significantly altered upon co-administration of the two agents, 24% increase in C(max) (p = 0.196) and 25% increase in AUC(0-24) (p = 0.212) values, although inter-subject variability was observed within this group.


CONCLUSIONS
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.
Krishna
Gopal
G
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. gopal.krishna@spcorp.com
Sansone-Parsons
Angela
A
Kantesaria
Bhavna
B
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019338:Polypharmacy; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D000935:Antifungal Agents; D014230:Triazoles; D010672:Phenytoin; C101425:posaconazole