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No Relevant Interactions Between Telaprevir and Two Newest Nonnucleosides Rilpivirine & Etravirine
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April
16-18, 2012, Barcelona
Mark Mascolini
Taking the anti-HCV protease inhibitor telaprevir with the nonnucleoside rilpivirine significantly boosted rilpivirine concentrations, but not to an extent judged clinically relevant, according to results of a study in healthy volunteers [1]. Both rilpivirine and etravirine lowered concentrations of telaprevir, but again not to clinically relevant extents.
Telaprevir, one of the first two anti-HCV protease inhibitors, shares metabolic pathways with etravirine and rilpivirine, the newest nonnucleosides licensed to treat HIV infection. All three antivirals are CYP3A substrates, meaning the CYP3A drug-metabolizing enzyme may affect their levels. Etravirine is an inducer of CYP3A and a substrate and inhibitor of two other metabolizing enzymes, CYP2C9 and CYP2C19. Etravirine may also inhibit the metabolism of other drugs because it inhibits P-glycoprotein, a drug transporter. Telaprevir inhibits CYP3A and P-glycoprotein.
Etravirine is licensed for antiretroviral-experienced people with HIV resistant to nonnucleosides and other antiretrovirals. Rilpivirine is licensed for antiretroviral-naive people but not for people with antiretroviral experience. Telaprevir is licensed for anti-HCV treatment-naive or experienced adults in combination with pegylated interferon and ribavirin [2].
Etravirine lowered telaprevir minimum concentration (Cmin) by 25%, maximum concentration (Cmax) by10%, and 8-hour area under the concentration-time curve (AUC) by 16%. None of these modest changes were considered clinically relevant. Telaprevir had no impact on concentrations of etravirine: least square mean (LSM) ratios and 90% confidence intervals for etravirine concentrations with versus without telaprevir were all within 80% to 125%.
When taken with telaprevir, rilpivirine concentrations were significantly higher than without telaprevir--1.93-fold for Cmin, 1.49-fold for Cmax, and 1.78-fold for 24-hour AUC. With rilpivirine coadministration, telaprevir levels were lower--11% for Cmin, 3% for Cmax, and 5% for 8-hour AUC. None of these changes in rilpivirine or telaprevir concentrations were judged clinically relevant.
Eighteen of 33 volunteers (55%) reported grade 1 headache. One person taking etravirine and telaprevir dropped out of the study with grade 2 myocardial ischemia, which was not judged to be related to either antiviral. The investigators detected no clinically significant lab abnormalities.
References
1. Kakuda T, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: a randomised, two-way crossover trial. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_18.
2. Vertex. INCIVEK (telaprevir) 375 mg tablets. http://www.incivek.com/.
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