Kuhn John G, Chang Susan M, Wen Patrick Y, Cloughesy Timothy F, Greenberg Harry, Schiff David, Conrad Charles, Fink Karen L, Robins H Ian, Mehta Minesh, DeAngelis Lisa, Raizer Jeffrey, Hess Kenneth, Lamborn Kathleen R, Dancey Janet, Prados Michael D
Pharmacotherapy Education and Research Center, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Clin Cancer Res. 2007 Dec 15;13(24):7401-6. doi: 10.1158/1078-0432.CCR-07-0781.
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.
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.
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.
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.
对比接受酶诱导抗癫痫药物（EIAED）的患者与接受非EIAEDs的患者，以明确替西罗莫司及其主要代谢产物西罗莫司的药代动力学特征。另一个目标是确定替西罗莫司或西罗莫司在脑肿瘤组织中是否能达到有效浓度。
未接受EIAEDs的复发性恶性胶质瘤患者最初每周静脉注射250mg替西罗莫司。由于出现无法耐受的副作用，随后剂量减至170mg。对于服用EIAEDs的患者，替西罗莫司的起始剂量为250mg，并按标准剂量递增，直至确定最大耐受剂量。在给予替西罗莫司后24小时内采集10份全血样本用于药代动力学评估。符合减瘤手术条件的患者在肿瘤切除前接受替西罗莫司治疗。采集全血和肿瘤组织进行分析。
在250mg的可比剂量水平下，两组患者的替西罗莫司和西罗莫司药代动力学变量存在显著差异。对于接受EIAEDs的患者，替西罗莫司的全身暴露量低1.5倍。同样，西罗莫司的峰值浓度和暴露量低2倍。在脑肿瘤标本中观察到了可测量的替西罗莫司和西罗莫司浓度。替西罗莫司的平均组织与全血比值为1.43，西罗莫司为0.84。
诱导细胞色素P450 3A4的药物，如EIAEDs，会显著影响替西罗莫司及其活性代谢产物西罗莫司的药代动力学。在最大耐受剂量为250mg时，EIAED组中替西罗莫司和西罗莫司的总暴露量低于最大耐受剂量为170mg的非EIAED组。然而，在各自剂量水平下，两组患者脑肿瘤组织中替西罗莫司和西罗莫司的浓度相对相当。有必要对组织进行雷帕霉素哺乳动物靶点关键调节因子（p70S6激酶和4E结合蛋白1）抑制的相关分析，以确定替西罗莫司暴露量改变的治疗意义。
