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First published on October 3, 2007, doi:10.1177/0091270007306957

The Journal of Clinical Pharmacology 2007;47:1430.

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©© 2007 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology , 10.1177/0091270007306957

Article

Pharmacokinetic Profile of Temsirolimus With Concomitant Administration of Cytochrome P450-Inducing Medications

Joseph Boni 1*, Cathie Leister 1, Jaime Burns 1, Maria Cincotta 1, Bruce Hug 1, and Laurence Moore 1

1 Wyeth Research

* To whom correspondence should be addressed. E-mail: bonij{at}wyeth.com.


  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.
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