Co-administration is not recommended due to the expected decrease of tenofovir alafenamide. Coadministration of rifabutin (300 mg once daily) and bictegravir (75 mg once daily) decreased bictegravir AUC, Cmin and Cmax by 38%, 56% and 20%, respectively (due to induction of CYP3A and P-gp). The interaction has not been studied with tenofovir alafenamide. Co-administration of rifabutin may decrease tenofovir alafenamide plasma concentrations.

Coadministration may decrease concentrations of bictegravir and tenofovir alafenamide. Coadministration with rifabutin is not recommended. Coadministration of rifabutin (300 mg once daily) and bictegravir (75 mg once daily) decreased bictegravir Cmax, AUC and Cmin by 20%, 38% and 56%, respectively.

Bictegravir Ctrough and viral load were evaluated in a prospective multi-centre study enrolling people with HIV on rifabutin containing regimen and bictegravir/emtricitabine/tenofovir alafenamide for at least 28 days. The primary endpoint was the proportion of bictegravir Ctrough levels above the protein adjusted 95% effective concentration (PA-EC95: 162 ng/mL). Between October 2023 and June 2025, 18 people with HIV (median age 41 years (IQR: 33-50), 94.4% men; 28% had HIV RNA below 50 copies/mL and 11% CD4 counts above 200 cells/mm3) received rifabutin containing therapy together with bictegravir/emtricitabine/tenofovir alafenamide. During rifabutin co-administration, bictegravir Ctrough level decreased significantly to 438.3 ng/mL (IQR 400-781) compared with 3261 ng/mL (IQR 1957-4696) without rifabutin representing a median reduction Ctrough reduction of 86% (IQR 72-90%). Despite this substantial decrease, only one (5.6%) participant had a bictegravir Ctrough level below 162 ng/mL but the participant remained virologically suppressed. During one-year of follow-up of concurrent use of rifabutin and bictegravir/emtricitabine/tenofovir alafenamide, the proportion of participants achieving plasma HIV viral loads below 50 copies/mL increased progressively: 50% at month 1, 62% at month 3, 86% at month, and 100% at months 9 and 12. The authors concluded that despite the significant reduction in bictegravir Ctrough levels, people with HIV receiving concurrent rifabutin can achieve and maintain viral suppression over one year of follow-up, with adequate bictegravir Ctrough levels for effective HIV control.

The analgesic metamizole is a moderate inducer of CYP3A4 and therefore has the potential to reduce the exposure of the CYP3A4/UGT1A1 substrate bictegravir. The magnitude of the drug-drug interaction between bictegravir and metamizole was evaluated using physiologically based pharmacokinetic (PBPK) modeling to inform clinical dosing decisions. PBPK models for bictegravir and metamizole were developed in PK-Sim using clinical and literature data. The bictegravir model was based on bictegravir plasma concentration-time data in three phase I studies, and the model verification was done using observed clinical drug-drug interaction data with known CYP3A4 modulators (bictegravir in combination with voriconazole, atazanavir or rifabutin). Metamizole inducing effect was verified using observed clinical dug-drug interaction data and the CYP3A4 probe substrate midazolam. Subsequent simulations evaluated the potential impact of metamizole 1000 mg four times daily (QID) administered for up to 10 days on the steady state plasma exposure of 50 mg bictegravir dosed once daily as a component of bictegravir/emtricitabine/tenofovir alafenamide. Simulations were performed in a virtual population of 100 individuals to assess interindividual variability and to contextualize predicted bictegravir exposures relative to clinical exposure ranges. The PBPK model for bictegravir and metamizole showed acceptable predictive performance with predicted-to-observed plasma concentration ratios within 2-fold across the evaluated datasets. Steady state simulation with metamizole predicted a reduction in the area under the concentration-time curve over a dosing interval (AUCtau), maximum (Cmax), and trough (Ctrough) bictegravir plasma levels by 38%, 23%, and 56%, respectively. Population simulations predicted a median bictegravir trough of 1309 ug/mL, with the 5th percentile at 0.554 ug/mL, remaining above the protein adjusted EC95 (162 ug/mL). The PBPK model predicted that metamizole at a maximum dose level resulted in a moderate reduction in bictegravir exposure. The predicted bictegravir trough remained above the protein adjusted EC95 threshold, with overall exposures exceeding those observed in clinical settings associated with the maintain of virologic suppression (e.g., during pregnancy). This suggests that the reduction in bictegravir exposure due to drug-drug interaction with metamizole may not warrant a dose adjustment.