BACKGROUND: Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals. METHODS: Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m(2)), obese (BMI 30-40 kg/m(2)), and morbidly obese (BMI 40-50 kg/m(2)) individuals. RESULTS: Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. CONCLUSIONS: The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m(2).