基于群体药动学模型的中国精神分裂症患者氨磺必利血药浓度仿真研究

Simulation Study on Blood Concentration of Amisulpride in Chinese Patients with Schizophrenia Based on Population Pharmacokinetic Model

目的:基于中国精神分症患者氨磺必利群体药动学特征模型,预测不同用药方案下患者服用氨磺必利后的稳态血药浓度,实施个体化给药方案设计。方法:回顾性收集55例患者的110个氨磺必利血药浓度值,运用已建立的氨磺必利群体药动学模型,通过第1个血药浓度值估算个体药动学参数,并以此预测后续血药浓度值,比较实际测量值与预测值,评估模型预测准确性,应用蒙特卡洛法仿真不同给药方案下氨磺必利稳态药物浓度范围。结果:预测的氨磺必利血药浓度与真实的血药浓度产生的误差的中位值为2.51 ng/ml,平均预测误差分别为2.78 ng/ml,均方根误差为75.8 ng/ml,表明该预测模型预测性与准确性良好。不同日剂量下氨磺必利的稳态谷浓度的存在显着差异。稳态谷浓度随着日剂量的增加而增加;当日剂量>600 mg时,氨磺必利稳态谷浓度通常会超过推荐治疗范围上限(320 ng/ml);相同日剂量下,给药时间间隔为24 h,谷浓度最低浓度波动度最大,随着给药频次的增加,谷浓度增加,浓度波动度变小。结论:基于群体药动学模型,可以准确地通过有限采血点预测个体的药物浓度范围,给药频次及给药剂量是影响氨磺必利血药浓度的主要因素。

OBJECTIVE:Based on the population pharmacokinetic model of of amisulpride in Chinese patients with schizophrenia,to predict the steady-state blood concentration of amisulpride in patients administrated by different medication regimens,and implement individualized dosing regimen design.METHODS:110 amisulpride blood concentration values of 55 patients were retrospectively collected,the established population pharmacokinetic model of amisulpride was adopted to estimate individual pharmacokinetic parameters through the first blood concentration value,so as to predict the follow-up blood concentration value and evaluate the accuracy of model prediction by comparing the real measured value and predicted value,and Monte Carlo method was used to simulate the steady-state drug concentration range of amisulpride under different medication regimens.RESULTS:The median of error between the predicted blood concentration and real blood concentration was 2.51 ng/ml,with the average prediction error was 2.78 ng/ml,the root-mean-square error was 75.8 ng/ml,which indicated the prediction model had good predictability and accuracy.There were significant differences in the steady-state trough concentration of amisulpride at different daily doses.The steady-state trough concentration increased with the increasing of daily dose;when the daily dose exceeds 600 mg,the trough concentration of amisulpride will usually exceed the upper limit of recommended treatment range(320 ng/ml);at the same daily dose,the dosing interval was 24 h,the lowest concentration of trough concentration fluctuated the most,with the administration frequency increased,the trough concentration also increased and the concentration fluctuation became smaller.CONCLUSIONS:Based on the population pharmacokinetic model,the individual drug concentration range can be accurately predicted through limited blood sampling points,the frequency and dosage of administration are the main factors affecting the blood concentration of amisulpride.