Cyclosporin A disposition following acute traumatic brain injury
Cyclosporin A disposition following acute traumatic brain injury
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DOI：
10.1089/neu.2006.23.109
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发表时间：
2006-01-01
影响因子：
4.2
通讯作者：
Hatton, J
中科院分区：
文献类型：
--
作者：
Empey, PE;McNamara, PJ;Hatton, J
虽然确切的作用机制仍有待确定，但环孢素A（CsA）已在动物模型中显示出潜在的神经保护作用。CsA在急性创伤性脑损伤（TBI）患者中的预测给药策略必须考虑急性期反应对药物处置的影响。为了表征急性TBI后早期CsA药代动力学参数，分析了入组II期剂量递增试验的患者的系列血液样本。在损伤后8小时内，30例急性重度TBI患者前瞻性随机分为3个队列（每个队列n = 8 CsA; n = 2安慰剂）。患者接受三种剂量之一（I = 0.625 mg/kg/剂; II = 1.25 mg/kg/剂; III = 2.5 mg/kg/剂）或安慰剂静脉给药，每12小时一次，持续72小时。在第I次给药前开始连续采血，并在完成6次给药后持续72 h。通过高效液相色谱法（HPLC）和紫外（UV）检测测定全血浓度。通过将浓度-时间曲线拟合至具有一级消除的二房室模型，测定每例患者的药代动力学参数。每个给药队列的平均曲线下面积和预测最大血药浓度增加（I = 9840 h* mug/L，398 mug/L; II = 18300 h* mug/L，645 mug/L; III = 32500 h* mug/L，1300 /mug/L）。全血清除率、稳态分布容积和β半衰期与剂量无关，且高于其他人群的已发表报告：分别为0.420 L/h/kg、5.91 L/kg和17.3 h。这些数据表明，急性重度TBI患者表现出更快的清除率和更大的CsA分布体积。本研究的药代动力学参数将指导未来前瞻性临床试验的剂量策略，以评估急性TBI后的CsA治疗。
Although the precise mechanism of action remains to be defined, Cyclosporin A (CsA) has demonstrated potential for neuroprotection in animal models. Predictive dosing strategies for CsA in acute traumatic brain injured (TBI) patients must account for the influence of the acute phase response on drug disposition. To characterize CsA pharmacokinetic parameters early following acute TBI, serial blood samples from patients enrolled into a Phase II dose-escalation trial were analyzed. Within eight hours of injury, thirty patients admitted with acute severe TBI were prospectively randomized into three cohorts (n = 8 CsA; n = 2 placebo per cohort) in this dose-escalation trial. Patients received one of three doses (I = 0.625 mg/kg/dose; II = 1.25 mg/kg/dose; III = 2.5 mg/kg/dose) or placebo intravenously every 12 h for 72 h. Serial blood collection began prior to dose I and continued for 72 h following the completion of six doses. Whole blood concentrations were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic parameters were determined for each patient by fitting the concentration-time profile to a two-compartmental model with first order elimination. Mean area under the curve and predicted maximal blood concentration increased with each dosing cohort (I = 9840 h*mu g/L, 398 mu g/L; II = 18300 h*mu g/L, 645 mu g/L; III = 32500 h*mu g/L, 1300 /mu g/L). Whole blood clearance, steady state volume of distribution, and beta half-life were independent of dose and higher than published reports from other populations: 0.420 L/h/kg, 5.91 L/kg, and 17.3 h, respectively. These, data show patients with acute severe TBI demonstrate a more rapid clearance and a larger distribution volume of CsA. Pharmacokinetic parameters derived from this study will guide dosing strategies for future prospective clinical trials evaluating CsA therapy following acute TBI.