Kharouba Maged, Cook Aaron M, Bastin Melissa L Thompson, Kutsogiannis Demetrios J, Mahmoud Sherif Hanafy
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Neurocrit Care. 2025 Sep 4. doi: 10.1007/s12028-025-02347-5.
Levetiracetam, a first-line antiseizure medication, is primarily eliminated through the kidneys, with approximately 66% renal elimination. Consequently, its pharmacokinetics are significantly influenced by kidney function. Augmented renal clearance (ARC), a condition characterized by renal hyperfiltration, is frequently observed in critical care settings and can profoundly impact the disposition of renally eliminated drugs such as levetiracetam. Our objectives were to characterize levetiracetam pharmacokinetics in neurocritical care patients, identify covariates significantly influencing drug clearance, and provide clinicians with optimal dosage recommendations in those with and without ARC.
This was a multicenter, prospective, observational study involving patients admitted to the participating centers with life-threatening neurological illnesses. Each participant had up to four plasma samples collected, and the samples were analyzed using a validated high-performance liquid chromatography method. The creatinine clearance (CL) of enrolled participants was measured using the 8-h urine collection method (measured CL [mCL]). Population pharmacokinetic modeling was performed using Monolix software. Monte Carlo simulations were performed to explore various dosage strategies and to suggest optimal levetiracetam regimens.
Our study included 50 patients, with 35 patients (70%) experiencing ARC. Trough levetiracetam levels were significantly lower in the ARC group compared with the no-ARC group (median [interquartile range] 4.4 [11.5] vs. 11.8 [19] mg/L, p value = 0.039, respectively). Population pharmacokinetic modeling showed levetiracetam clearance at 4.6 ± 2.97 L/h and volume of distribution at 0.56 ± 0.63 L/kg, following a one-compartment model. The mCL significantly affected levetiracetam clearance. Simulations indicated that an initial 500 mg twice daily (BID) dosage is insufficient. Patients with mCL ≥ 90 mL/min/1.73 m, including patients with ARC, may need at least 1500 mg BID, whereas those with mCL 60-89 mL/min/1.73 m may require an initial dosage of 1250 mg BID.
Augmented renal clearance significantly impacts the pharmacokinetics of levetiracetam by enhancing clearance. Dosing simulations revealed the inadequacy of the initial 500 mg BID regimen, indicating a minimum dosage of 1500 mg BID is necessary for patients experiencing ARC to achieve reference range concentrations.
左乙拉西坦是一种一线抗癫痫药物，主要通过肾脏排泄，约66%经肾脏清除。因此，其药代动力学受肾功能的显著影响。增强肾清除率（ARC）是一种以肾超滤为特征的情况，在重症监护环境中经常出现，并且会深刻影响经肾脏排泄的药物（如左乙拉西坦）的处置。我们的目标是描述神经重症监护患者中左乙拉西坦的药代动力学，确定显著影响药物清除率的协变量，并为有或无ARC的患者提供最佳剂量建议。
这是一项多中心、前瞻性、观察性研究，涉及入住参与中心的患有危及生命的神经系统疾病的患者。每位参与者最多采集4份血浆样本，并使用经过验证的高效液相色谱法对样本进行分析。使用8小时尿液收集法测量入组参与者的肌酐清除率（CL）（测量的CL [mCL]）。使用Monolix软件进行群体药代动力学建模。进行蒙特卡洛模拟以探索各种给药策略并提出最佳左乙拉西坦治疗方案。
我们的研究纳入了50名患者，其中35名患者（70%）出现ARC。ARC组的左乙拉西坦谷浓度显著低于无ARC组（中位数[四分位间距]分别为4.4 [11.5] 与11.8 [19] mg/L，p值 = 0.039）。群体药代动力学建模显示，按照一室模型，左乙拉西坦清除率为4.6 ± 2.97 L/h，分布容积为0.56 ± 0.63 L/kg。mCL显著影响左乙拉西坦清除率。模拟表明，初始每日两次（BID）500 mg的剂量不足。mCL≥90 mL/min/1.73 m²的患者，包括有ARC的患者，可能需要至少每日两次1500 mg的剂量，而mCL为60 - 89 mL/min/1.73 m²的患者可能需要初始剂量每日两次1250 mg。
增强肾清除率通过提高清除率显著影响左乙拉西坦的药代动力学。给药模拟显示初始每日两次500 mg方案不足，这表明对于出现ARC的患者，每日两次至少1500 mg的剂量对于达到参考范围浓度是必要的。
