Clinical Evaluation of Drug-Drug Interactions Between Bictegravir and Strong Inhibitors/Inducers of the CYP3A4, UGT1A1, or P-gp Pathways.

Abstract

In addition to antiretroviral therapy (ART), people with HIV often take medications to treat comorbidities. It is therefore important to assess these medications for potential drug-drug interactions, which may affect the safety and efficacy of ART. Three phase I studies were conducted in adult participants without HIV. The pharmacokinetics (PK) and safety of bictegravir (administered alone or as bictegravir/emtricitabine/tenofovir alafenamide fumarate [TAF]) were assessed when co-administered with inducers (rifampin, rifabutin, and rifapentine) or inhibitors (atazanavir ± cobicistat, darunavir + cobicistat, and voriconazole) of cytochrome P450 3A4 (CYP3A4), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), and/or P-glycoprotein (P-gp). PK parameters were compared using analysis of variance to calculate geometric least-square mean ratios and 90% confidence intervals. Overall, 172 participants were enrolled. CYP3A4 inhibition (voriconazole) moderately increased bictegravir exposure (61% increase in area under the concentration-time curve extrapolated to infinity [AUC_inf]), whereas dual CYP3A4 and UGT1A1 inhibition (atazanavir) led to a 315% increase in AUC_inf. P-gp inhibition had a minimal effect on bictegravir exposure. Induction of CYP3A4, UGT1A1, and/or P-gp by rifampin, rifabutin, and rifapentine led to decreases in bictegravir exposure and/or trough concentration (C_trough). Bictegravir and bictegravir/emtricitabine/TAF were well tolerated alone and in combination with other drugs. Inhibition of CYP3A4 or UGT1A1 alone is unlikely to cause clinically meaningful changes in bictegravir exposure; only potent inhibitors of both pathways are expected to significantly affect bictegravir PK. Induction of CYP3A4 with/without UGT1A1 significantly influenced bictegravir PK, although C_trough remained above the protein-adjusted 95% effective concentration. These findings should be considered when co-administering medications with bictegravir.