Purpose: Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM).
Methods: We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite - VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature.
Results: The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4- and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates. This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus.
Conclusions: The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir.