阿立哌唑在8岁以上儿童和青少年精神障碍患者中的群体药动学研究

目的: 建立阿立哌唑(aripiprazole,ARI)在8岁以上儿童和青少年精神障碍患者群体中的药动学模型,评价和优化给药方案。方法: 采用二维液相串联质谱法检测197例8~18岁儿童和青少年精神障碍患者口服ARI后体内原形药物ARI和主要活性代谢产物脱氢阿立哌唑(dehydroaripiprazole,DARI)的药物浓度数据,收集相关临床资料,采用非线性混合效应建模法建立群体药动学(PPK)模型。基于最终模型参数,模拟和评价不同特征患者的ARI最佳给药方案。结果: 最终模型显示体质量和联合使用丙戊酸镁是影响患者ARI清除率的显著性因素。当未联用丙戊酸镁时,30~50 kg患者给予ARI 10 mg,qd或5 mg,bid方案,51~70 kg患者给予ARI 12.5 mg,qd或5 mg,bid方案,71~110 kg患者给予ARI 15 mg,qd或7.5 mg,bid方案时;当联用丙戊酸镁时,30~50 kg患者给予ARI 12.5 mg,qd或5 mg,bid方案,51~70 kg患者给予ARI 15 mg,qd或7.5 mg,bid方案,71~110 kg患者给予ARI 17.5 mg,qd或7.5 mg,bid方案时;ARI或ARI+DARI稳态谷浓度高于目标范围下限的概率大于85%,高于目标范围上限的概率不超过10%,可保证临床疗效和安全性,为优化方案。结论: 该研究建立了一个可同时预测ARI及其代谢物DARI浓度的联合药动学模型,根据模型制定了不同体质量和联合用药分层患者的ARI优化给药方案,为临床药物治疗决策提供参考。

Population pharmacokinetics of aripiprazole in phychiatric children and adolescents over 8 years old

OBJECTIVE To establish a population pharmacokinetics (PPK) model of aripiprazole (ARI) in children and adolescents with mental disorders over 8 years old, in order to evaluate and optimize the dosing regimens.METHODS Two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) was used to detect the concentrations of parent drug ARI and its main active metabolite dehydroaripiprazole (DRAI) in 197 children and adolescents with mental disorders aged 8-18 years after oral administration. The clinical data were collected. The PPK model was established by nonlinear mixed effect modeling. The optimal administration schemes of ARI in the patients with different characteristics were simulated and evaluated based on the final model parameters.RESULTS The final model showed that body weight and combining with magnesium valproate were the significant covariates affecting the clearance of ARI. The simulation results showed that without magnesium valproate combination, the patients ranging from 30 to 50 kg were given 10 mg, qd or 5 mg, bid, the patients ranging from 51 to 70 kg were given 12.5 mg, qd or 5mg, bid, and the patients ranging from 71 to 100 kg were given 15 mg, qd or 7 mg, bid. When combining with magnesium valproate, the patients ranging from 30 to 50 kg were given 12.5 mg, qd or 5mg, bid, those ranging from 51 to 70 kg were given 15 mg, qd or 7.5 mg, bid, and those ranging from 71 to 110 kg were given 17.5 mg, qd or 7.5 mg, bid. The probability of ARI or ARI+DARI steady-state valley concentration higher than the lower limit of the target range was more than 85%, and the probability of higher than the upper limit of the target range was not more than 10%, which could ensure the clinical efficacy and safety, which were the optimal schemes.CONCLUSION The study developed a combined pharmacokinetics model that can simultaneously predict the concentrations of ARI and its metabolite DARI, and the optimal dosing regimens for different body weights and various drug combinations can be formulated according to the PPK model of ARI, which provide reference for clinical treatment decisions.