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Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bonij@wyeth.com
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/m(2) temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (C(max)) by 36% and increased volume of distribution by 99%. Sirolimus C(max) 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 C(max) and AUC but decreased sirolimus C(max) and AUC by 65% and 56%, respectively. Rifampin decreased AUC(sum) 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.
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