University of Queensland Centre for Clinical Research, The University of Queensland, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, QLD, 4029, Australia.
Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
Clin Pharmacokinet. 2021 May;60(5):655-664. doi: 10.1007/s40262-020-00979-8. Epub 2021 Jan 11.
Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens.
This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations.
A two-compartment model best described the concentration-time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h, clearance 2.5 ± 1.1 L/h, central volume of distribution 8.9 ± 3.0 L/h, and transfer rate constraints of 1.8 ± 1.1 h from central to peripheral compartments and 0.7 ± 0.3 h from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance.
Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.
严重创伤患者表现出增强的肾清除率，这可能改变肾脏消除药物的剂量需求。本研究旨在建立用于严重创伤性脑损伤和伴有蛛网膜下腔出血的动静脉畸形患者的左乙拉西坦群体药代动力学模型，并描述最佳的给药方案。
这是一项前瞻性开放标签观察性研究。纳入标准为无肾功能障碍且接受左乙拉西坦治疗的严重创伤性脑损伤或伴有蛛网膜下腔出血的成年危重症患者。对左乙拉西坦的血清浓度进行分析，以建立群体药代动力学模型并进行剂量模拟。
两室模型最能描述 30 例患者的浓度-时间数据。平均±标准差参数估计值为生物利用度（F）为 0.8±0.2，吸收速率常数为 2.4±2 h，清除率为 2.5±1.1 L/h，中央分布容积为 8.9±3.0 L/h，中央到外周室的转移率常数为 1.8±1.1 h，外周到中央室的转移率常数为 0.7±0.3 h。对于模拟的间歇性给药方案，平均而言，尿肌酐清除率每增加 40 ml/min/1.73 m2，谷浓度中位数就降低 50%。对于某些程度的增强肾清除率，需要模拟剂量至少 6 g/天。
伴有增强肾清除率的严重创伤性脑损伤和伴有蛛网膜下腔出血的患者有无法达到目标左乙拉西坦血药浓度的风险。我们建议根据测量的肌酐清除率进行剂量调整，和/或在可用时进行治疗药物监测，以最大程度降低癫痫发作的风险。
