Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir with Rifampicin

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Gausi, K ORCID: 0000-0002-9002-8087, Mugerwa, H, Siccardi, M ORCID: 0000-0002-3539-7867, Montanha, MC, Lamorde, M, Wiesner, L ORCID: 0000-0002-9070-8699, D'Avolio, A, McIlleron, H, Wilkins, E, De Nicolò, A ORCID: 0000-0002-5973-9948 et al (show 5 more authors) , Maartens, G ORCID: 0000-0003-3080-6606, Khoo, S ORCID: 0000-0002-2769-0967, Kityo, C, Denti, P ORCID: 0000-0001-7494-079X and Waitt, C ORCID: 0000-0003-0134-5855 (2024) Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir with Rifampicin Clinical Infectious Diseases, 78 (5). pp. 1246-1255. ISSN 1058-4838, 1537-6591

Text Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir With Rifampicin.pdf - Open Access published version Download (962kB)

Abstract

Background. Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. Methods. DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. Results. We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia. Conclusions. Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target.

Item Type:	Article
Uncontrolled Keywords:	tuberculosis, HIV, drug-drug interaction, pharmacokinetics, Africa CID specifications
Depositing User:	Symplectic Admin
Date Deposited:	03 Jul 2024 12:44
Last Modified:	28 Feb 2026 16:27
DOI:	10.1093/cid/ciad700
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3182199
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