Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study

Abstract

Ritonavir-boosted atazanavir is a victim of drug-drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir/ritonavir 300/100 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC-MS/MS methods to evaluate steady-state concentrations at the end of each period. Atazanavir/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI₉₀ 0.72-1.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir/ritonavir concentrations in PBMC. The study confirms that increasing the ATV/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.

Figure 1

Depiction of the individual trends in intra‐PBMC concentrations of atazanavir (panel a) and 90% CI of the geomean concentration (panel b) changes throughout the study. Dotted lines represent the boundaries of the CI, solid line is the geomean. PK1 = ATV/r 300/100 mg q.d.; PK2 = addition of RIF 600 mg q.d. and DTG 50 mg b.i.d.; PK3 = ATV/r dose escalation to 300/100 mg b.i.d.; PK4 = RIF dose increased to 1,200 q.d. Concentration at PK2 was determined at 12 hours, despite q.d. dosing.

Figure 2

Depiction of the individual trends in intra‐PBMC concentrations of dolutegravir (panel a) and 90% CI of the geomean concentration (panel b) changes throughout the study. Dotted lines represent the boundaries of the CI, solid line is the geomean. PK2 = addition of RIF 600 mg q.d. and DTG 50 mg b.i.d.; PK3 = ATV/r dose escalation to 300/100 mg b.i.d.; PK4 = RIF dose increased to 1,200 q.d.