766b
Hepatic Transaminase Elevations and Gastrointestinal Intolerance when HIV-negative Healthy Volunteers on Rifampin add Twice-daily Atazanavir ( 300 mg)/Ritonavir ( 100 mg): ACTG Protocol A5213
David Haas*1, S Koletar2, L Laughlin2, M Kendall3, C Suckow3, J Gerber4, A Zolopa5, R Bertz6, M Child6, E Acosta7, and the A5213 Study Team
1Vanderbilt Univ Sch of Med, Nashville, TN, US; 2Ohio State Univ, Columbus, US; 3Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 4Univ of Colorado Hlth Sci Ctr, Denver, US; 5Stanford Univ, Palo Alto, CA, US; 6Bristol-Myers Squibb, Princeton, NJ, US; and 7Univ of Alabama at Birmingham, US
Background: Safe and effective strategies are needed
to treat HIV and Mycobacterium tuberculosis co-infection. Rifampin (RIF) induces hepatic cytochrome CYP3A, lowering plasma concentrations of HIV protease
inhibitors. Previously reported data from A5213 were based on 10 healthy,
HIV-seronegative volunteers taking ATV 300 mg every 12 hours for 8 to 11 days, then
atazanavir (ATV) 300 mg every 12 hours and RIF 600 mg every 24 hours for 11 to 15
days, then ATV 400 mg every 12 hours and RIF 600 mg every 24 hours for 8 to 11
days. Study drugs were safe and well tolerated, but ATV did not maintain
adequate plasma exposure. A5213 was revised to test whether adequate plasma ATV
concentrations could be safely achieved with RTV boosting and twice-daily
dosing among healthy volunteers who were first administered RIF.
Methods: We planned to enroll 14 evaluable HIV–
healthy adults into an open-label pharmacokinetic interaction study involving 3
sequential periods of RIF ± ATV/RTV. ATV and RTV were taken orally with food every
12 hours; RIF was taken in the morning as follows: period 1, RIF 600 mg every 24
hours for 8 to 11 days; period 2, RIF 600 mg every 24 hours, ATV 300 mg every 12
hours and RTV 100 mg every 12 hours for 11 to 15 days; period 3, RIF 600 mg every
24 hours, ATV 400 mg every 12 hours and RTV 100 mg every 12 hours for 8 to 11
days. Pharmacokinetic sampling was to be done at the end of each period
Results: A total of 3 participants
enrolled into this revision of A5213. All tolerated RIF for 8 days during
Period 1. However, within 12 hours of the initial dose of ATV (300 mg)/RTV (100
mg) in period 2, all developed nausea and vomiting. After no more than 7 doses
of ATV/RTV all developed hepatic transaminase elevations. The highest ALT value
in each participant was 792 (grade 4), 173 (grade 2), and 154 (grade 2). All
discontinued study drug, symptoms resolved, and ALT values subsequently normalized.
The study was closed to further enrollment based on these results.
Conclusions: Among 3 healthy volunteers receiving
once-daily RIF, the addition of twice-daily ATV/RTV caused nausea, vomiting and
hepatic transaminase elevations. This is similar to previous reports in which healthy
volunteers taking RIF then added lopinavir/RTV or saquinavir/RTV. We
hypothesize that pre-induction of CYP3A4 by RIF generates a toxic metabolite of
RTV. Alternatively, inhibition of CYP3A4 and/or a drug transporter by RTV may
block clearance of a toxic metabolite of RIF.
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