Drug Interactions between Agenerase and nevirapine

ADJUST DOSE: Coadministration with nevirapine may significantly decrease the plasma concentrations of most protease inhibitors (PIs) except ritonavir. The mechanism is nevirapine induction of PI metabolism via CYP450 3A4. In seven patients with advanced HIV disease who were starting dual nucleoside analogs and nelfinavir (750 mg three times a day) as salvage therapy, mean nelfinavir peak plasma concentration (Cmax), 8-hour area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) decreased by 43%, 50% and 53%, respectively, following addition of nevirapine 3 days later (200 mg daily for 2 weeks followed by 200 mg twice daily for 1 week). The time to reach Cmax was reduced from 4 to 2 hours. Autoinduction of nelfinavir metabolism may have played a role, as supported by a study involving 23 patients in which pre- and post-nevirapine plasma levels of nelfinavir taken presumably after both drugs have reached steady state demonstrated no evidence of a significant pharmacokinetic interaction. In another study, nevirapine decreased the median steady-state Cmax, AUC and Cmin of indinavir (800 mg three times a day) by 11%, 27% and 47%, respectively, after 4 weeks of coadministration in 17 HIV-infected subjects. However, antiretroviral response was significantly greater following addition of nevirapine. Ritonavir added as a pharmacokinetic booster has been shown to counteract the inductive effect of nevirapine in some cases, although a decrease in lopinavir concentrations was demonstrated in a pediatric study involving Kaletra and nevirapine.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if nevirapine is prescribed in combination with PIs, particularly if only one PI is used in the antiretroviral regimen. PI dosages may need to be increased when coadministered with nevirapine, although appropriate dosages with respect to safety and efficacy have not been established.