Drug Interactions between amprenavir and fosphenytoin

MONITOR: In the absence of ritonavir as a pharmacokinetic booster, coadministration of amprenavir or fosamprenavir with phenytoin may result in decreased plasma concentrations of amprenavir. The proposed mechanism is phenytoin induction of amprenavir metabolism via CYP450 3A4. In contrast, when ritonavir is present, phenytoin levels may be decreased due to induction of CYP450 2C9 metabolism by ritonavir. In a pharmacokinetic study involving 14 subjects, coadministration of phenytoin (300 mg once a day) in combination with fosamprenavir plus ritonavir (700 mg and 100 mg twice a day, respectively) for 10 days resulted in a 20% reduction in phenytoin peak plasma concentration (Cmax), a 22% reduction in systemic exposure (AUC), and a 29% reduction in trough plasma concentration (Cmin). Amprenavir AUC and Cmin increased by approximately 20%.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, amprenavir and fosamprenavir should be used cautiously with phenytoin if ritonavir is not coadministered as a boosting agent. Antiretroviral response should be monitored more closely whenever phenytoin is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary. However, if ritonavir is also prescribed, the potential for reduced therapeutic effects of phenytoin should be considered. Phenytoin dosage may need to be increased if patient demonstrates subtherapeutic phenytoin levels or experiences loss of seizure control. No change in the dosages of fosamprenavir (or amprenavir) and ritonavir is necessary during coadministration with phenytoin.