Model-based evaluation of the interaction between ritonavir-boosted atazanavir and rifampicin in Ugandan adults with HIV

Aim: Concomitant treatment of tuberculosis (TB) and human immunodeficiency virus (HIV) is complicated by drug-drug interactions (DDI). This analysis aimed to characterize the DDI between ritonavir-boosted atazanavir (ATV/r) and rifampicin in plasma and peripheral blood mononuclear cells (PBMC). Methods: The DERIVE study (NCT04121195) recruited Ugandan adults with HIV (not TB) on ATV/r-based second-line antiretroviral therapy, and collected intensive plasma and PBMC pharmacokinetic samples during four visits: (i) standard-dose ATV/r 300/100 mg QD, (ii) same ATV/r regimen adding rifampicin 600 mg QD, (iii) doubling ATV/r to BID with rifampicin 600 mg QD and (iv) ATV/r 300/100 mg BID with rifampicin increased to 1200 mg QD. ATV/r plasma and PBMC concentrations were analysed with population pharmacokinetic modelling in NONMEM. Results: Twenty-six participants (23 female) were enrolled, with median age and weight of 44 years and 67 kg, respectively. A two-compartment model with an effect-compartment effectively described atazanavir concentrations in plasma and PBMC. Rifampicin increased atazanavir clearance threefold, while decreasing its bioavailability and absorption rate. Doubling dosing frequency of ATV/r largely mitigated the interaction with rifampicin, restoring the proportion of simulated participants achieving the targeted trough atazanavir concentration of 0.014 mg/L to 99%. Rifampicin did not affect the ratio of atazanavir concentration between PBMCs and plasma. Conclusion: Metabolic induction by rifampicin accounts for the decrease in plasma exposure of ATV/r. Doubling the ATV/r dosing frequency to BID effectively mitigated this interaction. The plasma exposure of ATV/r mirrored that in PBMCs, suggesting that for these drugs, plasma concentrations provide a reliable reflection of site-of-action exposures.