Han Xiaolu, Hong Xiaoxuan, Li Xianfu, Wang Yuxi, Wang Zengming, Zheng Aiping
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Haidian District, Beijing 100850, China.
Troops 32104 of People's Liberation Army of China, Alashan League 735400, China.
Children (Basel). 2021 Oct 22;8(11):950. doi: 10.3390/children8110950.
For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC to deduce the optimal dosage of amlodipine for children aged 1-16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg for ages 2-6 years and -0.0028 × Age + 0.1148 (mg/kg) for ages 7-16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.
对于儿童这一持续发育的特殊人群，合理的给药策略是临床治疗的关键。准确的剂量预测有助于在儿科治疗中最大化疗效并最小化痛苦。本研究收集了236名中国成年男性的氨氯地平药代动力学（PK）数据，并使用GastroPlus™建立了成人的生理药代动力学（PBPK）模型。基于肝脏与身体大小及酶代谢构建了儿科PBPK模型，类似地利用AUC推导1 - 16岁儿童氨氯地平的最佳剂量。绘制了2岁、6岁、12岁、16岁和25岁儿童的连续给药曲线，并制定了6岁儿童的个体化给药方案。结果表明，儿童无法建立统一的异速放大规则。2 - 6岁儿童的最佳剂量为0.10 mg·kg，7 - 16岁儿童的最佳剂量为 - 0.0028×年龄 + 0.1148（mg/kg），r = 0.9941。不同组间连续给药趋势一致。对于一名6岁儿童，采用维持剂量2.30 mg，初始剂量增加2.00 mg，治疗剂量增加1.00 mg以维持稳定的血浆浓度。基于酶代谢的PBPK模型能够准确预测儿科患者氨氯地平药代动力学参数的变化。它可用于支持儿科临床治疗方案的优化。
