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DOUBLING THE DOSE OF RALTEGRAVIR (RAL) DOES NOT INCREASE TROUGH LEVELS IN THE PRESENCE OF RIFAMPIN (RIF)
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Reported by Jules Levin
ICAAC/IDSA Oct 2008 Wash DC
Diana M Brainard1, Amelia Petry1, William D Hanley1, Larissa A Wenning1, Bo Jin1, Sheila Breidinger1, Jolene K Berg2, Neal Azrolan1, Julie A Stone1,
John A Wagner1, Jeffrey A Chodakewitz1, Marian Iwamoto1
1Merck & Co., Inc, Whitehouse Station, NJ 2CEDRA Clinical Research, LLC, San Antonio, TX
AUTHOR CONCLUSIONS
Coadministration of 800mg q12hr RAL with 600mg qd RIF is generally well-tolerated.
Although doubling the RAL dose to 800 mg q12hr when coadministered with
RIF compensates for the effect of RIF on RAL exposure (AUC0-12hr), it does
not overcome the effect of RIF on RAL trough concentrations (C12hr).
--- Trough concentrations remain above the protein- adjusted IC95 (31nM).
The decrease in C12hr is similar to what is seen with coadministration of 400
mg q12hr RAL and RIF.
Although trough concentrations have not been shown to correlate with efficacy, caution should be used when RAL is coadministered with RIF until additional clinical information is available.
Abstract
Background: RAL is a HIV-1 integrase strand transfer inhibitor with potent in vitro and in vivo activity against HIV-1. RIF is a known potent broad inducer of drug metabolizing enzymes including UGT1A1, the enzyme primarily responsible for the metabolism of RAL. A prior investigation of 400 mg RAL coadministered with RIF demonstrated a reduction in RAL plasma trough concentrations (C12hr GMR 400 mg RAL + RIF/400 mg RAL [90% CI]=0.39 [0.30, 0.51]). This study was conducted to assess whether a doubling of the therapeutic dose of RAL (to 800 mg) when coadministered with RIF results in plasma levels of RAL equivalent to plasma levels when 400 mg RAL is administered alone.
Methods: Open-label, 2-period, fixed- sequence study in 18 healthy adults. Period 1: subjects received 400 mg RAL q12h for 4 days. Period 2: same subjects received 800 mg RAL q12h and 600 mg RIF qd for 14 days (except Day 14 PM dose of RAL). Clinical safety evaluations were performed throughout the study. RAL plasma concentration data were collected.
Results: No serious adverse experiences (AEs) were reported and no discontinuations due to clinical or laboratory AEs classified as possibly or definitely related to study drug. Compared to 400 mg RAL administered
alone, multi-dose administration of RIF with 800 mg RAL resulted in lower RAL C12h values (GMR 800 mg RAL + RIF/ 400 mg RAL [90% CI]) = 0.47 [0.36, 0.61], and similar to slightly higher RAL AUC0-12h and Cmax values (GMR [90% CI]) = 1.27 [0.94, 1.71] and 1.62 [1.12, 2.33].
Conclusions: Doubling the RAL dose to 800 mg when coadministered with RIF does not overcome the effect of RIF on RAL trough concentrations (which nevertheless remain above the protein adjusted IC95). The decrease in C12h is similar to what is seen with coadministration of 400 mg RAL and RIF. Although trough concentrations have not been shown to correlate with efficacy, caution should be used when RAL is coadministered with RIF.
Introduction
RAL is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro and in vivo activity against HIV-1.
RAL is primarily metabolized by glucuronidation via UGT1A1.
RIF, a broad inducer of drug metabolizing enzymes including UGT1A1, is often used for the treatment of tuberculosis infection in HIV patients.
A previous study demonstrated a moderate decrease in RAL plasma concentrations when a single dose of 400 mg RAL was administered with RIF in healthy adults.1
The study presented here was designed to evaluate the safety, tolerability and pharmacokinetics of 800 mg twice-daily RAL plus RIF to that of 400 mg twice-daily RAL alone in healthy adults.
References
1 Iwamoto M, Wenning LA, Liou SY, Kost JT, Mangin E, Strohmaier KM, Marbury TC, Stone J, Gottesdiener KM, Wagner JA. Rifampin (RIF) modestly reduces plasma levels of MK-0518. 8th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland, 2006. Abstract #P299.
2 Merschman, SA, Vallano PT, Wenning, LA, Matuszewski BK, Woolf EJ. Determination of the HIV integrase inhibitor, MK- 0518 (raltegravir), in human plasma using 96-well liquid-liquid extraction and HPLC-MS/MS. J Chromatog B 2007; 857: 15-19.
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