title: Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus.
abstract: Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C(max)) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC(sum) (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.
authors.affiliation: Department of Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bonij@wyeth.com
authors.forename: J P
authors.initials: JP
authors.lastname: Boni
authors.forename: C
authors.initials: C
authors.lastname: Leister
authors.forename: J
authors.initials: J
authors.lastname: Burns
authors.forename: B
authors.initials: B
authors.lastname: Hug
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C401859:temsirolimus; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D020123:Sirolimus