Stoschus Maximilian, Schmidbauer Moritz L, Starp Johannes, Kunst Stefan, Gakis Georgios, Paal Michael, Vogeser Michael, Scharf-Janssen Christina, Liebchen Uwe, Dimitriadis Konstantinos
Department of Neurology, Ludwig Maximilian University (LMU) Hospital, LMU Munich, Munich, Germany.
Department of Anesthesiology, Ludwig Maximilian University (LMU) Hospital, LMU Munich, Munich, Germany.
Epilepsia. 2025 Jun 26. doi: 10.1111/epi.18517.
Current weight-based dosing fails to account for pharmacokinetic variability in refractory and superrefractory status epilepticus (RSE, SRSE). However, understanding pharmacokinetics in critically ill patients with varying degrees of organ dysfunction can improve both safety and efficacy. Hence, this study aims to quantify key pharmacokinetic variabilities to enable individualized dosing in RSE and SRSE.
Patients with RSE and SRSE admitted to a neurointensive care unit of a tertiary academic center were retrospectively screened for therapeutic drug monitoring (TDM) samples of phenobarbital. Demographics, laboratory data, comedication, and dosing history were collected from electronic health records. Using a nonlinear mixed effects modeling approach via MONOLIX, a population pharmacokinetic model was developed. Optimal dosing regimens were simulated based on estimated parameters, with target attainment calculated for trough plasma phenobarbital concentrations within 18-40 mg/L.
Thirty-seven patients contributed 301 TDM samples. Oral bioavailability (96%), volume of distribution (V; 34.3 L), and total body clearance (CL; .38 L/h) were consistent with nonintensive care literature data. Ideal body weight (IBW) implemented as allometric scaling was the only significant covariate improving model fit, demonstrating a positive correlation with the required phenobarbital dose. Simulations identified optimal 12-h dosing strategies. Oral and intravenous dosing showed minor differences in loading doses but identical maintenance doses, with no significant impact on target attainment for both administration methods. As shown by the coefficients of variation (CVs), intensive care patients exhibited high interindividual (81.36% CV on V, 41.36% CV on CL) and interoccasion variability (36.85% CV on CL), resulting in low target attainment in simulated patients (~40%).
The pharmacokinetic model characterized phenobarbital pharmacokinetics in patients with RSE and SRSE, showing high oral bioavailability and IBW's impact on V and CL. High pharmacokinetic variability led to low target attainment. Model-informed precision dosing might improve target attainment in the future.
目前基于体重的给药方式未能考虑难治性和超难治性癫痫持续状态（RSE，SRSE）患者的药代动力学变异性。然而，了解不同程度器官功能障碍的重症患者的药代动力学，可提高安全性和有效性。因此，本研究旨在量化关键药代动力学变异性，以实现RSE和SRSE的个体化给药。
对一所三级学术中心神经重症监护病房收治的RSE和SRSE患者进行回顾性筛查，获取苯巴比妥的治疗药物监测（TDM）样本。从电子健康记录中收集人口统计学、实验室数据、合并用药及给药史。通过MONOLIX采用非线性混合效应建模方法，建立群体药代动力学模型。基于估计参数模拟最佳给药方案，并计算18 - 40mg/L的苯巴比妥谷血浆浓度的达标率。
37例患者提供了301份TDM样本。口服生物利用度（96%）、分布容积（V；34.3L）和全身清除率（CL；0.38L/h）与非重症监护文献数据一致。作为异速生长标度实施的理想体重（IBW）是唯一能改善模型拟合的显著协变量，与所需苯巴比妥剂量呈正相关。模拟确定了最佳的12小时给药策略。口服和静脉给药在负荷剂量上有微小差异，但维持剂量相同，两种给药方式对达标率均无显著影响。变异系数（CV）显示，重症监护患者个体间（V的CV为81.36%，CL的CV为41.36%）和个体内（CL的CV为36.85%）变异性较高，导致模拟患者的达标率较低（约40%）。
该药代动力学模型表征了RSE和SRSE患者的苯巴比妥药代动力学，显示出高口服生物利用度以及IBW对V和CL的影响。高药代动力学变异性导致达标率较低。模型指导的精准给药未来可能会提高达标率。
