基于蒙特卡洛模拟法评估普瑞巴林在不同肾功能局灶性癫痫患者中官方剂量的合理性

Evaluation of the Rationality of the Official Dose of Pregabalin for Focal Epilepsy in Patients with Different Renal Functions Using Monte Carlo Simulation

目的综合蒙特卡洛模拟(monte carlo simulation,MCS)和敏感性分析重新评估局灶性癫痫患者中普瑞巴林推荐剂量的适宜性。方法设定正常肾功能患者多次服用批准剂量达稳态后产生的药时⁃曲线下面积(plasma concentration⁃time curve,AUC)为目标治疗范围,计算各给药方案的达标概率(probability of target attainment,PTA),并以PTA>90%作为优选方案的标准。结果除终末期肾病(end⁃stage renal disease,ESRD)外,其他肾功能损害亚组中批准剂量的PTA均大于90%。此外,敏感性分析显示性别,体重,食物状态,给药间隔和肌酐清除率的变化未显著影响推荐剂量的PTA。结论模拟结果支持普瑞巴林在轻度、中度与重度肾功能不全患者中的FDA批准剂量,但在ESRD患者中的批准剂量偏高。

OBJECTIVE To reassess the appropriateness of recommended doses of pregabalin in patients with focal epilepsy using a combination of Monte Carlo simulation(MCS)and sensitivity analysis.METHODS The study defined the area under the plasma concentration⁃time curve(AUC)at steady⁃state for patients with normal re⁃nal function at the approved dose as the target therapeutic range and calculated the probability of target attainment(PTA)for each dosing regimen.The regimen with PTA>90%was identified as the optimal regimen.RESULTS The PTA of the approved dosage was>90%in all renal impairment subgroups,except for the end⁃stage renal disease group.Furthermore,sensitivity analysis revealed that sex,body weight,food status,dosing interval,and changes in cre⁃atinine clearance did not significantly impact the PTA for the recommended dose.CONCLUSION The analysis supported the approved dose of pregabalin in patients with moderate and severe renal impairment,but the approved dose was high in patients with mild renal impairment and end⁃stage renal disease.