Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir
Article first published online: 22 SEP 2009
© 2010 Pfizer Inc.. Journal compilation © 2010 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 69, Issue 1, pages 51–57, January 2010
How to Cite
Andrews, E., Glue, P., Fang, J., Crownover, P., Tressler, R. and Damle, B. (2010), Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir. British Journal of Clinical Pharmacology, 69: 51–57. doi: 10.1111/j.1365-2125.2009.03546.x
- Issue published online: 23 DEC 2009
- Article first published online: 22 SEP 2009
- Received 27 April 2009Accepted17 August 2009
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor.
• Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs.
• As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them.
WHAT THIS STUDY ADDS
• Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean Cmax, and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively.
• Co-administration was generally safe and well tolerated in healthy subjects.
• These changes are not likely to be clinically relevant, thus no dose adjustment is necessary.
AIMS To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir.
METHODS In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1–3 raltegravir 400 mg q12h, days 4–5 washout, days 6–11 maraviroc 300 mg q12h, and days 12–14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.
RESULTS For maraviroc, the test/reference % ratio (95% CI) for AUCτ was 85.8 (78.7, 93.5), for Cmax was 79.5 (64.8, 97.5) and for Cmin was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUCτ was 63.3 (41.0, 97.6), for Cmax was 66.8 (37.1, 120.0) and for Cmin was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUCτ divided by 12) were >100 ng ml−1, the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean Cmin decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.
CONCLUSIONS Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.