Pharmacokinetic Profile of Temsirolimus With Concomitant Administration of Cytochrome P450‐Inducing Medications1

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Abstract
Temsirolimus is a novel inhibitor of the mammalian target of rapamycin, with antitumor activity in advanced tumors. Because temsirolimus and its metabolite, sirolimus, are cytochrome P450 (CYP) 3A4/5 substrates, the potential exists for interaction with drugs that induce CYP3A activity, including enzyme inducers and rifampin. Cancer patients received once‐weekly intravenous (IV) 220 mg/m2 temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (Cmax) by 36% and increased volume of distribution by 99%. Sirolimus Cmax and area under the concentration‐time curve (AUC) were decreased by 67% and 43%, respectively. In healthy adult subjects, coadministration of 25‐mg intravenous temsirolimus with rifampin had no significant effect on temsirolimus Cmax and AUC but decreased sirolimus Cmax and AUC by 65% and 56%, respectively. Rifampin decreased AUCsum by 41%. Temsirolimus was well tolerated in both studies. If concomitant agents with CYP3A induction potential are used, higher temsirolimus doses may be needed to achieve adequate tumor tissue drug levels.