Critical drug-drug interactions (DDI) exist between rifampicin and boosted protease inhibitors. Hepatotoxicity has occurred frequently in DDI studies of adjusted doses of protease inhibitors with rifampicin. We aimed to determine if dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin used at standard and double doses.
DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people living with HIV without tuberculosis on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed at steady-state: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Due to the potential risk of sub-therapeutic atazanavir concentrations with rifampicin, dolutegravir 50 mg BID was co-administered. Target atazanavir level against HIV is a minimum effective concentration (MEC) of 0.15 mg/L. Noncompartmental analysis was used to describe the pharmacokinetic data. Concentrations below the lower limit of quantification (LLOQ) of 0.03 mg/L were replaced by LLOQ/2.
26 participants were enrolled with a median (range) weight and age of 44 (28 – 61) years and 67 (50 – 75) kg, respectively, and 23 (88%) were female. Compared with PK1, atazanavir concentrations were significantly reduced at PK2: geometric mean ratio (GMR, 90%CI) of Cmin and AUC24 were 0.04 (0.03 – 0.05 and 0.15 (0.12 – 0.18), respectively. The escalation to BID dosing (PK3) when compared to PK1, had a GMR of 0.83 (0.68 – 1.02) and 1.08 (0.97 – 1.21), respectively. The comparable exposures were maintained with double doses of rifampicin, GMR of Cmin, and AUC24 0.81 (0.67 – 1.00) and 1.01 (0.93 – 1.09) compared to PK1, respectively. The percentage of participants with concentrations below the MEC target was 4%, 100%, 23%, and 19% during PK1, PK2, PK3, and PK4 visits, respectively. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia.
These results indicate that increasing the dose of atazanavir/ritonavir to twice daily was well-tolerated and achieved acceptable atazanavir plasma concentrations
Figure 1: Beeswarm plot of atazanavir Cmin and AUC0-24 across the 4 PK visits with geometric mean ratios of the three visits vs first visit at the top of the figure. The horizontal and vertical line represent geometric mean and range respectively. The Cmin of 0.015 belong to values below the lower limit of quantification