title: Disposition of desipramine, a sensitive cytochrome P450 2D6 substrate, when coadministered with intravenous temsirolimus.
abstract: OBJECTIVE
  Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), is approved for treatment of renal cell carcinoma. In vitro studies with pooled human liver microsomes showed that temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 isozyme (K(i) = 1.5 and 5 microM, respectively), indicating potential for pharmacokinetic interaction with agents that are substrates of CYP2D6.
  
  
  METHODS
  This 2-period study in healthy subjects investigated the pharmacokinetics of a single oral 50-mg dose of the CYP2D6 substrate desipramine, first without and subsequently with a single coadministered i.v. 25-mg dose of temsirolimus.
  
  
  RESULTS
  The study population consisted of 25 males and 1 female; 10 were black, 12 were white, and 4 were of other races. Plasma and whole blood samples were available from all 26 subjects in period 1 following oral desipramine and from 23 subjects in period 2 following oral desipramine and i.v. temsirolimus coadministration. The 90% confidence intervals for least squares geometric mean ratios of desipramine and 2-hydroxy-desipramine C(max), AUC(T), and AUC were within 80-125%, indicating that parameter differences did not manifest into clinically relevant exposure changes. A single i.v. 25-mg dose of temsirolimus, alone or with desipramine, was well tolerated in healthy subjects.
  
  
  CONCLUSIONS
  A single i.v. 25-mg dose of temsirolimus did not alter disposition of desipramine. Temsirolimus i.v. 25 mg may be safely administered with agents metabolized through the CYP2D6 pathway, but vigilance for drug interaction is warranted in patients with advanced malignancies.
authors.affiliation: Department of Early Development and 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: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Jaime
authors.initials: J
authors.lastname: Burns
authors.forename: Ronald
authors.initials: R
authors.lastname: Jordan
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: William
authors.initials: W
authors.lastname: DeMaio
authors.forename: Bruce
authors.initials: B
authors.lastname: Hug
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C401859:temsirolimus; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine; D020123:Sirolimus