Drug Interaction Report

MONITOR: Coadministration with modafinil (the racemate) or armodafinil (the R-enantiomer) may decrease the plasma concentrations of protease inhibitors (PIs). The mechanism involves induction of intestinal CYP450 3A4-mediated first-pass metabolism by modafinil and armodafinil, with possible secondary induction of hepatic 3A4 metabolism. Significant intestinal metabolism appears to occur with indinavir and saquinavir but has not been studied with other PIs. Conversely, PIs may increase the plasma concentrations of modafinil via inhibition of hepatic CYP450 3A4 metabolism. The clinical significance is unknown. However, the possibility of prolonged and/or increased pharmacologic effects of modafinil should be considered.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with decreased or subtherapeutic antiretroviral drug levels, caution is advised if modafinil or armodafinil must be used in patients treated with PIs, particularly if they are using only one PI in their antiretroviral regimen. Clinical monitoring for altered effects of both modafinil and the PI may be appropriate following addition or withdrawal of one or the other drug.

Administration with food may delay the absorption of modafinil (the racemate) and armodafinil (the R-enantiomer) without significantly affecting their overall bioavailability. According to the product labeling, modafinil's absorption may be delayed by approximately one hour if taken with food. Similarly, the time to reach peak plasma concentration (Tmax) of armodafinil may be delayed by approximately 2 to 4 hours in the fed state.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.