Drug Interactions between lenacapavir and nirmatrelvir / ritonavir

MONITOR: Coadministration with lenacapavir may increase the plasma concentrations of drugs that are substrates of the efflux transporters P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP). Lenacapavir is an inhibitor of P-gp and BCRP. In pharmacokinetic studies in subjects without HIV, coadministration of oral lenacapavir (600 mg twice daily for 2 days, then single 600 mg dose) with the P-gp substrate tenofovir alafenamide increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of tenofovir alafenamide by 24% and 32%, respectively. In addition, under similar conditions, coadministration of lenacapavir with the BCRP substrate rosuvastatin (single 5 mg dose) led to an increase in rosuvastatin Cmax and AUC by 57% and 31%, respectively. However, these changes for tenofovir alafenamide and rosuvastatin are not reported to be clinically significant.

MANAGEMENT: Caution and monitoring are advised if lenacapavir is used concomitantly with drugs that are substrates of the transporters P-gp and/or BCRP, particularly sensitive substrates, or those with a narrow therapeutic range. Dose adjustments or alternative therapy may be necessary if an interaction is suspected.

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.