Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma.
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.
Kuhn
John G
JG
Pharmacotherapy Education and Research Center, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. Kuhn@uthscsa.edu
Chang
Susan M
SM
Wen
Patrick Y
PY
Cloughesy
Timothy F
TF
Greenberg
Harry
H
Schiff
David
D
Conrad
Charles
C
Fink
Karen L
KL
Robins
H Ian
HI
Mehta
Minesh
M
DeAngelis
Lisa
L
Raizer
Jeffrey
J
Hess
Kenneth
K
Lamborn
Kathleen R
KR
Dancey
Janet
J
Prados
Michael D
MD
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
D000927:Anticonvulsants; D000970:Antineoplastic Agents; C401859:temsirolimus; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus