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The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers

Article date: February 2013

By: Varun Garg, Gurudatt Chandorkar, Yijun Yang, Nathalie Adda, Lindsay McNair, Katia Alves, Frances Smith, Rolf P. G. Heeswijk, in Volume 75, Issue 2, pages 431-439


• Telaprevir is a hepatitis C virus protease inhibitor for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. In vitro studies indicated that CYP3A was the major cytochrome P‐450 (CYP) isozyme involved in the metabolism of telaprevir. It is important to understand the potential for drug–drug interactions of telaprevir when it is co‐administered with CYP3A inhibitors or inducers.


• CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. After a single dose, telaprevir exposure is increased when ketoconazole, a strong CYP3A inhibitor, is co‐administered. However, at steady‐state, telaprevir exposure is less likely to be affected by CYP3A inhibitors.

AIM To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.

METHOD Results from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz.

RESULTS A single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least‐squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for Cmax and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co‐administration of rifampicin at steady‐state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for Cmax and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co‐administered at steady‐state, with GLSMRs of 0.91 (0.81, 1.02) for Cmax, 0.53 (0.44, 0.65) for Cmin, and 0.74 (0.65, 0.84) for AUC(0,8 h).

CONCLUSION CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.

DOI: 10.1111/j.1365-2125.2012.04345.x

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