Review of drug interactions with telaprevir and antiretrovirals
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Study Design
The manufacturer lists the effect of ritonavir on telaprevir pharmacokinetics (PK). Examined was a single dose of each drug (100mg of ritonavir on 750mg of telaprevir) and repeated dosing (ritonavir 100mg q12 for 14 days and telaprevir 750mg q12 for 14 days). As well, in a phase 1, open-label, multiple-dose, randomized, parallel-group study of 18 healthy male volunteers, the pharmacokinetics of three dosing regimens of telaprevir with or without ritonavir where examined over 14 days. The treatment groups were divided into A (telaprevir 250mg q12 and ritonavir 100mg q12), B (telaprevir 750mg q12 and ritonavir 100mg q12), and C (telaprevir 750mg q8h).
Study Results
Repeated dosing lowered average telaprevir concentrations. Cmax, Cavg,ss, and Cmin were decreased by 15%, 24% and 32%, respectively. Versus an increase in the average telaprevir Cmax and AUC by 30% and 100% for the single dose. In the phase 1 study, it was found that on day 14, group C (telaprevir 750mg q8h) had the highest average PK parameters, followed by group B, then A. It was also found that group C had the largest accumulation of telaprevir (AUCday14/AUCday1) over the 14 days, followed by group A, and lastly group B. However, group B had the largest ritonavir exposure over the 14 days when compared to group A.
Study Conclusions
The possible reasons for these results are not definitive. The authors stated the outcome could be due to ritonavir enzyme and/or P-gp induction, telaprevir CYP3A self-inhibition and non-CYP mediated pathways of telaprevir metabolism after repeat dosing, or displacement of telaprevir from protein-binding sites by ritonavir. Also, it was suggested that telaprevir has dose-dependent CYP3A inhibition.
References
Van Heeswijk RP, Beumont M, Kauffman RS, Garg V. Review of drug interactions with telaprevir and antiretrovirals. Antiviral Therapy. 2013; 4: 553-560.
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