Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model.
Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model.
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DOI：
10.1007/s00280-015-2711-1
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发表时间：
2015-05
影响因子：
3
通讯作者：
Warren KE
中科院分区：
文献类型：
--
作者：
Cole DE;Lester-McCully CM;Widemann BC;Warren KE
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包括手术、放疗和化疗，但手术切除并不总是一种选择，化疗药物的疗效也有限。最近的研究重点是针对关键致瘤途径的分子靶向治疗。多种肿瘤类型，包括高级神经胶质瘤和儿童脑桥神经胶质瘤，表现出 Akt 激活。 Perifosine 是一种口服生物可利用的合成烷基磷脂和强效 Akt 抑制剂，已在一些临床前模型中表现出活性，但在脑桥神经胶质瘤基因工程小鼠模型中缺乏活性。我们在非人灵长类动物模型中评估了口服哌立福辛的血浆和脑脊液药代动力学，以评估中枢神经系统渗透性。将哌立福辛以 7.0 mg/kg 的单剂量口服给予三只成年恒河猴。连续收集配对血浆和脑脊液样本长达 64 天。通过经过验证的 HPLC/串联质谱分析对哌立福辛进行定量。使用非房室方法估计药代动力学参数。根据浓度-时间曲线下的面积计算脑脊液渗透率。血浆峰值浓度 (Cmax) 范围为 11.7–19.3 µM，并在超过 28 天的时间内保持 >1 µM。达到 Cmax 的时间 (Tmax) 为 19 小时。中位（范围）AUCPl 为 3148（2502-4705）μM/h，中位（范围）终末半衰期（t1/2）为 193（170-221）小时。血浆清除率为 494 (329–637) mL/h/kg。 CSF 峰值浓度为 4.1–10.1 nM（Tmax 64–235 小时）。 CSF AUC 和 t1/2 分别为 6358 (2266–7568) nM/h 和 277 (146–350) h。 CSF 中的哌立福辛浓度保持在 nM 以上超过 35 天。平均脑脊液渗透率为 0.16%。全身给药后，哌立福辛的中枢神经系统渗透性较差。然而，单次口服剂量后，血浆和脑脊液中的水平可在较长时间内（> 2 个月）测量到。
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 (Cmax) ranged from 11.7–19.3 µM, and remained >1 µM for >28 days. Time to Cmax (Tmax) was 19 h. The median (range) AUCPl was 3148 (2502–4705) µM/h, with a median (range) terminal half-life (t1/2) of 193 (170–221) h. Plasma clearance was 494 (329–637) mL/h/kg. Peak CSF concentrations were 4.1–10.1 nM (Tmax 64–235 h). CSF AUCs and t1/2 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.
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影响因子：
11.2
作者：
Momota, H;Nerio, E;Holland, EC
通讯作者：
Holland, EC
在遗传学和组织学精确的脑干神经胶质瘤模型中，辐射和perifosine的临床前评估。
影响因子：
11.2
作者：
Becher OJ;Hambardzumyan D;Walker TR;Helmy K;Nazarian J;Albrecht S;Hiner RL;Gall S;Huse JT;Jabado N;MacDonald TJ;Holland EC
通讯作者：
Holland EC
影响因子：
11.5
作者：
Hennessy, Bryan T.;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
15.9
作者：
Mueller, Sabine;Phillips, Joanna;Haas-Kogan, Daphne A.
通讯作者：
Haas-Kogan, Daphne A.
影响因子：
3.4
作者：
Schmidt-Hieber, Martin;Dabrowski, Robert;Blau, Igor W.
通讯作者：
Blau, Igor W.