# 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.

## Key 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.