title: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications.
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/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.
authors.affiliation: Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bonij@wyeth.com
authors.forename: Joseph
authors.initials: J
authors.lastname: Boni
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Jaime
authors.initials: J
authors.lastname: Burns
authors.forename: Maria
authors.initials: M
authors.lastname: Cincotta
authors.forename: Bruce
authors.initials: B
authors.lastname: Hug
authors.forename: Laurence
authors.initials: L
authors.lastname: Moore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011494:Protein Kinases / Q000378:metabolism; D012293:Rifampin / Q000493:pharmacokinetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D012293:Rifampin; D020123:Sirolimus