Drug Interactions between amoxicillin / omeprazole / rifabutin and lenacapavir

GENERALLY AVOID: Coadministration with drugs that are combined P-glycoprotein (P-gp) and moderate inducers of CYP450 3A4 or sole moderate inducers of CYP450 3A4 may decrease the plasma concentrations of lenacapavir and result in a potential loss of virologic response. The proposed mechanism is increased clearance due to induction of the isoenzyme CYP450 3A4, which is partly responsible for the metabolism of lenacapavir and induction of the P-gp transporter of which lenacapavir is a substrate. In pharmacokinetic studies conducted in fasted subjects without HIV, coadministration of a single oral dose of lenacapavir 300 mg with the combined P-gp and moderate inducer of CYP450 3A4 efavirenz 600 mg once daily decreased the systemic exposure (AUC) and peak plasma concentration (Cmax) of lenacapavir by approximately 56% and 36%, respectively.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of lenacapavir with drugs that are combined P-gp and moderate inducers of CYP450 3A4 or sole moderate inducers of CYP450 3A4 should generally be avoided.

MONITOR: Coadministration with lenacapavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. According to the manufacturer, lenacapavir is a moderate inhibitor of CYP450 3A4 and due to its long half-life after subcutaneous administration, it may increase the exposure to and risk of adverse reactions to drugs primarily metabolized by CYP450 3A4 that are initiated within 9 months after the last subcutaneous lenacapavir dose. In pharmacokinetic studies in fed subjects without HIV, coadministration of oral lenacapavir (600 mg twice daily for 2 days, then a single 600 mg dose) with the sensitive CYP450 3A4 substrate midazolam (single 2.5 mg dose orally at the same time as the single lenacapavir dose) led to an increase in midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.9-fold and 3.6-fold, respectively.

MANAGEMENT: Caution is advised if lenacapavir is coadministered with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic index. Due to its long half-life, the effect may persist for up to 9 months after the last subcutaneous dose, so caution and monitoring for adverse effects are also advised during this time. The prescribing information for the coadministered drug should also be consulted for specific dosing recommendations.