Premium
Pharmacokinetic Profile of Temsirolimus With Concomitant Administration of Cytochrome P450‐Inducing Medications 1
Author(s) -
Boni Joseph,
Leister Cathie,
Burns Jaime,
Cincotta Maria,
Hug Bruce,
Moore Laurence
Publication year - 2007
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270007306957
Subject(s) - temsirolimus , pharmacology , sirolimus , cyp3a4 , pharmacokinetics , cyp3a , concomitant , medicine , cytochrome p450 , chemistry , discovery and development of mtor inhibitors , pi3k/akt/mtor pathway , biochemistry , metabolism , apoptosis
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.