Dose Escalation Study to Determine the Pharmacokinetics of Atazanavir Administered With RIfampicin to HIV Positive Adults on sEcond-line ART Regimen With Suppressed HIV-1 Viral Load

Summary

The standard treatment for TB consists of rifampicin (RIF) as part of the regimen. However, due to drug-drug interactions (DDI), the bioavailability of PIs is greatly reduced when co-administered with RIF necessitating use of higher doses of the PI to overcome this effect. However, the potential effect of this increased dose on the DDI with bPIs is uncertain. Though some data has been collected that shows safe use of higher doses of LPV to overcome the DDI with standard doses of RIF in HIV-infected individuals, no substantive data has been collected on ATV to correctly adjust its dose when co-administered with RIF-based TB treatment. Physiologically-based pharmacokinetic (PBPK) modelling was developed to understand ATV and RIF DDIs, and identified potential dosing strategies to overcome this challenge in adults and special populations under workpackage 1 of the VirTUAL consortium. From this work, it is anticipated that the dose of ATV/r should be increased from 300/100 once daily to 300/100mg twice daily in order to overcome the interaction with rifampicin and attain therapeutic plasma concentrations. This dose escalation trial aims to: 1. Evaluate the steady state plasma and intracellular PK of ATV/r, when administered in adjusted (PBPK model-predicted) doses concurrently with RIF 2. Evaluate the safety and tolerability / acceptability of the adjusted dose of ATV/r that provides the therapeutic concentration when co-administered with RIF. 3. Evaluate the concentration of dolutegravir (DTG) and RIF when co-administered and explore the potential DDI with ATV/r

Timeline

Start

2020-10-30

Primary completion

2022-05-20

Completion

2023-05-20

Publications

• Gausi K, Mugerwa H, Siccardi M, Montanha MC, Lamorde M, Wiesner L, D'Avolio A, McIlleron H, Wilkins E, De Nicolo A, Maartens G, Khoo S, Kityo C, Denti P, Waitt C. Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir With Rifampicin. Clin Infect Dis. 2024 May 15;78(5):1246-1255. doi: 10.1093/cid/ciad700.
• Urbaniak A, Thummel KE, Alade AN, Rettie AE, Prasad B, De Nicolo A, Martin JH, Sheppard DN, Jarvis MF. Experimental pharmacology in precision medicine. Pharmacol Res Perspect. 2023 Dec;11(6):e01147. doi: 10.1002/prp2.1147. No abstract available.

Drugs

Indications