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.