Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.
Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.
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DOI：
10.1007/s10637-015-0311-x
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发表时间：
2016-02
影响因子：
3.4
通讯作者：
Widemann BC
中科院分区：
文献类型：
--
作者：
Shah NN;Cole DE;Lester-McCully CM;Wayne AS;Warren KE;Widemann BC
长春新碱硫酸长春新碱脂质体注射剂(VSLI，MARQIBO®)是FDA批准的标准长春新碱鞘磷脂/胆固醇脂质体的胶囊制剂。临床药代动力学研究表明，VSLI是一种长循环、缓释制剂，仅限于血浆中，缺乏有关脑脊液(CSF)药代动力学的先前数据。我们报告了使用已建立的非人灵长类动物(NHP)模型比较静脉注射长春新碱和静脉注射长春新碱的脑脊液和血浆药代动力学参数的结果。在交叉药代动力学研究中，三只成年雄性恒河猴(猕猴)被给予长春新碱或VSLI 0.1 mg/kg(1.2 mg/m2人体当量剂量)。分别于输液前、输液结束(EOI)及输液结束后不同时间点采集连续配对的血液和脑脊液标本。标准长春新碱的血浆消失曲线呈多指数曲线，中位半衰期(t1/2)为4.8min(4.4-5.0min)，中位半衰期(t1/2)为24.3h，而VSLI计算的中位数t1/2为17.9h(13.9-21.5h)。单个NHP的ClVCR：ClVSLI的比值分别为300、463和477。在给药后，在任何脑脊液样本中都没有检测到长春新碱。结论在三种动物中，分别作为各自的对照，我们证明了VSLI的药代动力学曲线显示，与标准水制剂相比，VSLI的总长春新碱的清除量明显延长(约低400倍)，从而加深了我们对VSLI药代动力学的理解。将VSLI作为标准长春新碱替代品的几项临床试验正在进行中。
Vincristine sulfate liposomes injection (VSLI, Marqibo®) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal fluid (CSF) pharmacokinetics are lacking. We report our results comparing CSF and plasma pharmacokinetic parameters of intravenous aqueous vincristine to intravenous VSLI using an established non-human primate (NHP) model. Three adult male rhesus monkeys (Macaca mulatta) were administered 0.1 mg/kg (1.2 mg/m2 human-equivalent dose) of vincristine or VSLI in a crossover pharmacokinetic study. Serial paired blood and CSF samples were obtained before infusion, at the end of infusion (EOI) and at various time points thereafter. In contrast to standard vincristine, which had a multi-exponential plasma disappearance curve with a median initial (EOI to 30 min post-infusion) half-life (T1/2) of 4.8 min (range, 4.4–5.0 min) and terminal T1/2 of 24.3 h, a near-monoexponential curve with a median T1/2 of 17.9 h (range, 13.9–21.5 h) hours was calculated with VSLI. The ratios Cl VCR:Cl VSLI for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample after administration of either formulation. Conclusions In three animals, each serving as their own control, we demonstrate that the pharmacokinetic profile of VSLI shows markedly prolonged clearance (approximately 400-fold lower) of total vincristine in comparison to the standard aqueous formulation, enhancing our understanding of VSLI pharmacokinetics. Several clinical trials incorporating VSLI as substitution for standard vincristine are in progress.
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影响因子：
3
作者：
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通讯作者：
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