Bictegravir (BIC; B) is a potent, once-daily, unboosted HIV integrase strand transfer inhibitor (INSTI) with a high barrier to resistance. BIC is coformulated with the NRTI backbone of emtricitabine/tenofovir alafenamide (F/TAF) into the single-tablet regimen, B/F/TAF for treatment of HIV-1 infection. BIC is primarily hepatically eliminated, with similar contributions by the drug metabolizing enzymes CYP3A and UGT1A1. Rifampin (RIF), a component of tuberculosis (TB) treatment, is a potent inducer of metabolizing enzymes. A previous study evaluating the coadministration of RIF with once-daily BIC showed a marked reduction in BIC concentrations. The present study evaluated the pharmacokinetics (PK) of BIC administered twice daily (BID) in combination with RIF.
Healthy subjects were enrolled into one of two cohorts (N=26/cohort). Cohort 1 subjects received B/F/TAF (50/200/25 mg) QD, 2 hours postprandial, for 28 days. Cohort 2 subjects received B/F/TAF BID plus RIF 600 mg QD, 2 hours postprandial, for 28 days. Intensive plasma sampling was conducted on Day 28 for determination of BIC primary PK parameters (AUC[sub]0-24h[/sub], C[sub]max[/sub], C[sub]trough[/sub]). Statistical comparisons for BIC were performed using geometric least squares mean (GLSM) ratios and associated 90% confidence intervals (CI) with B/F/TAF BID plus RIF in Cohort 2 as the test treatment and B/F/TAF QD in Cohort 1 as the reference treatment. Safety was assessed throughout the study and follow up.
Following coadministration of B/F/TAF BID plus RIF for 28 days, the BIC AUC0-24h and Cmax were decreased approximately 61% and approximately 47%, respectively, as compared with B/F/TAF QD administration alone (Table 1). Although the observed BIC Ctrough in all subjects was above the protein adjusted 95% effective concentration (paEC95) (162 ng/mL) following B/F/TAF BID plus RIF in Cohort 2, the resulting geometric least squares mean BIC Ctrough was approximately 80% lower, as compared with that observed following B/F/TAF QD in Cohort 1 (Table 1). All treatments were well tolerated and all subjects completed the study.
The present study results confirm the drug drug interaction between RIF and BIC. These findings show that twice daily administration of B/F/TAF with RIF does not mitigate the induction effect sufficiently to yield BIC Ctrough concentrations associated with the B/F/TAF registrational Phase 3 studies.