Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.
Clin Infect Dis
; 2023 Nov 20.
Article
em En
| MEDLINE
| ID: mdl-37982585
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 HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed PK1 300/100â mg OD (baseline); PK2 300/100â mg OD with rifampicin 600â mg; PK3 300/100â mg BID with rifampicin 600â mg OD; PK4 300/100â mg BID with rifampicin 1200â mg OD. Dolutegravir 50â mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014â 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, while 65% of PK2 Ctau were below the limit of quantification (0.03â mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia.CONCLUSIONS:
Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article