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

TL;DR

This study examines how the HIV drug atazanavir interacts with the TB drug rifampicin in Ugandan adults, finding that doubling the dose frequency helps maintain effective drug levels.

Contribution

The study introduces a dosing adjustment strategy to mitigate the drug interaction between ATV/r and rifampicin in HIV patients.

Findings

Rifampicin increases atazanavir clearance and reduces its bioavailability and absorption rate.

Doubling ATV/r dosing frequency to BID largely restores effective trough concentrations in most participants.

The ratio of atazanavir concentration between PBMCs and plasma remains unaffected by rifampicin.

Abstract

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).

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.

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.

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.

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