Cole Diane E, Lester-McCully Cynthia M, Widemann Brigitte C, Warren Katherine E
Pharmacology and Experimental Therapeutics, POB, NCI, NIH, Bethesda, MD, 20892, USA.
Cancer Chemother Pharmacol. 2015 May;75(5):923-8. doi: 10.1007/s00280-015-2711-1. Epub 2015 Mar 5.
Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration.
Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves.
Peak plasma concentrations (C max) ranged from 11.7-19.3 µM, and remained >1 µM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502-4705) µM/h, with a median (range) terminal half-life (t 1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T max 64-235 h). CSF AUCs and t 1/2 were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over nM for >35 days. The mean CSF penetration was 0.16 %.
CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose.
中枢神经系统肿瘤在组织学和生物学上具有异质性。恶性肿瘤的标准治疗方法包括手术、放疗和化疗，但手术切除并非总是可行的选择，化疗药物的疗效也有限。最近的研究集中在针对关键致癌途径的分子靶向治疗上。包括高级别胶质瘤和儿童脑桥胶质瘤在内的几种肿瘤类型表现出Akt激活。哌立福新是一种口服生物可利用的合成烷基磷脂和有效的Akt抑制剂，在一些临床前模型中已显示出活性，但在脑桥胶质瘤的基因工程小鼠模型中无活性。我们在非人灵长类动物模型中评估了口服哌立福新的血浆和脑脊液药代动力学，以评估其对中枢神经系统的穿透性。
对三只成年恒河猴口服给予哌立福新，单剂量为7.0mg/kg。连续采集配对的血浆和脑脊液样本，最长达64天。用经过验证的高效液相色谱/串联质谱分析法对哌立福新进行定量。使用非房室方法估算药代动力学参数。根据浓度-时间曲线下面积计算脑脊液穿透率。
血浆峰浓度（Cmax）范围为11.7 - 19.3μM，且在>28天内保持>1μM。达峰时间（Tmax）为19小时。血浆药时曲线下面积（AUCPl）的中位数（范围）为3148（2502 - 4705）μM/h，终末半衰期（t1/2）的中位数（范围）为193（170 - 221）小时。血浆清除率为494（329 - 637）mL/h/kg。脑脊液峰浓度为4.1 - 10.1 nM（Tmax为64 - 235小时）。脑脊液AUC和t1/2分别为6358（2266 - 7568）nM/h和277（146 - 350）小时。脑脊液中哌立福新浓度在>35天内保持超过 nM。平均脑脊液穿透率为百分之0.16。
全身给药后哌立福新对中枢神经系统的穿透性较差。然而，单次口服给药后，血浆和脑脊液中的药物水平在较长时间（>2个月）内均可测量。
