title: Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma.
abstract: OBJECTIVE
  To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue.
  
  
  METHODS
  Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis.
  
  
  RESULTS
  Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus.
  
  
  CONCLUSIONS
  Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.
authors: Pharmacotherapy Education and Research Center, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. Kuhn@uthscsa.edu
authors: John G
authors: JG
authors: Kuhn
authors: Susan M
authors: SM
authors: Chang
authors: Patrick Y
authors: PY
authors: Wen
authors: Timothy F
authors: TF
authors: Cloughesy
authors: Harry
authors: H
authors: Greenberg
authors: David
authors: D
authors: Schiff
authors: Charles
authors: C
authors: Conrad
authors: Karen L
authors: KL
authors: Fink
authors: H Ian
authors: HI
authors: Robins
authors: Minesh
authors: M
authors: Mehta
authors: Lisa
authors: L
authors: DeAngelis
authors: Jeffrey
authors: J
authors: Raizer
authors: Kenneth
authors: K
authors: Hess
authors: Kathleen R
authors: KR
authors: Lamborn
authors: Janet
authors: J
authors: Dancey
authors: Michael D
authors: MD
authors: Prados
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000601:surgery; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005910:Glioma / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; C401859:temsirolimus; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus