Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir.

TitleHepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir.
Publication TypeJournal Article
Year of Publication2009
AuthorsHaas DW, Koletar SL, Laughlin L, Kendall MA, Suckow C, Gerber JG, Zolopa AR, Bertz R, Child MJ, Hosey L, Alston-Smith B, Acosta EP
Corporate AuthorsA5213 StudyTeam
JournalJ Acquir Immune Defic Syndr
Volume50
Issue3
Pagination290-3
Date Published2009 Mar 1
ISSN1525-4135
KeywordsAdult, Antitubercular Agents, Atazanavir Sulfate, Female, Gastrointestinal Tract, HIV Protease Inhibitors, Humans, Liver, Male, Oligopeptides, Pyridines, Rifampin, Ritonavir
Abstract

BACKGROUND: Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P4503A by rifampin markedly lowers HIV protease inhibitor plasma concentrations.

METHODS: This phase 1, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included 3 sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours.

RESULTS: Upon adding atazanavir and ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated.

CONCLUSIONS: Coadministration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies, which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.

DOI10.1097/QAI.0b013e318189a7df
Alternate JournalJ. Acquir. Immune Defic. Syndr.
PubMed ID19194314
PubMed Central IDPMC2653210
Grant ListAI068634 / AI / NIAID NIH HHS / United States
AI068636 / AI / NIAID NIH HHS / United States
AI069439 / AI / NIAID NIH HHS / United States
AI069556 / AI / NIAID NIH HHS / United States
AI32775 / AI / NIAID NIH HHS / United States
AI69452 / AI / NIAID NIH HHS / United States
AI694742 / AI / NIAID NIH HHS / United States
KL2 RR024977 / RR / NCRR NIH HHS / United States
RR024975 / RR / NCRR NIH HHS / United States
TL1 RR024978 / RR / NCRR NIH HHS / United States
U01 AI032775 / AI / NIAID NIH HHS / United States
U01 AI032775-10 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
U01 AI068634-03 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
U01 AI068636-03 / AI / NIAID NIH HHS / United States
U01 AI069439 / AI / NIAID NIH HHS / United States
U01 AI069439-03 / AI / NIAID NIH HHS / United States
U01 AI069450 / AI / NIAID NIH HHS / United States
U01 AI069450-03 / AI / NIAID NIH HHS / United States
U01 AI069452 / AI / NIAID NIH HHS / United States
U01 AI069452-03 / AI / NIAID NIH HHS / United States
U01 AI069474 / AI / NIAID NIH HHS / United States
U01 AI069474-03 / AI / NIAID NIH HHS / United States
U01 AI069556-03 / AI / NIAID NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
UL1 RR024975-01 / RR / NCRR NIH HHS / United States
UL1 RR024975-017782 / RR / NCRR NIH HHS / United States