Shimizu Makiko, Uehara Shotaro, Ohyama Katsuhiro, Nishimura Haruka, Tanaka Yoichi, Saito Yoshiro, Suemizu Hiroshi, Yoshida Sayaka, Yamazaki Hiroshi
Lab. of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Japan.
Central Institute for Experimental Animals, Japan.
Drug Metab Dispos. 2023 Oct 25;52(1):DMD-AR-2023-001481. doi: 10.1124/dmd.123.001481.
Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized-liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and -demethylated metabolites in Japanese children aged 8-14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects' small body size and normal or reduced P450 2D6-dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and -demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring or alleles might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and -desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers, compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers. Validated simple pharmacokinetic models are able to predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine P450 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and -desmethylatomoxetine in spot urine/plasma samples could be a simple semi-quantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.
托莫西汀是一种细胞色素P450（P450）2D6探针底物，也是一种已获批准用于治疗注意力缺陷多动障碍的药物。在这项人源化肝脏小鼠研究中，观察到了托莫西汀与P450 2D6探针药物帕罗西汀之间的相互作用。通过放大在不存在或存在帕罗西汀的情况下获得的人源化肝脏小鼠数据，建立了基于人体生理的药代动力学（PBPK）模型。这些模型可以解释8至14岁日本儿童中托莫西汀及其主要的4-羟基化和去甲基化代谢物的药物监测结果，并可用于帮助确定正确的剂量以及评估临床结果。简单PBPK模型（使用反映受试者小体型以及正常或降低的P450 2D6依赖性清除率的输入参数）的结果与13名儿科参与者中托莫西汀及其4-羟基化和去甲基化代谢物的单点测量血浆浓度总体一致。意外的高肝暴露，可能在携带 或 等位基因的中间代谢者患者中出现，这可能部分解释了在日本不良事件数据库中记录的单独使用托莫西汀时的不良反应。参与者的稳态单点药物监测数据表明，在单独规定剂量的托莫西汀作用下，托莫西汀广泛生物转化为4-羟基托莫西汀。这些结果还表明，与广泛代谢者中两种主要代谢物和底物的广泛浓度范围相比，儿科患者即时尿样和/或血浆样本中4-羟基托莫西汀和去甲托莫西汀浓度比的相对较窄范围可能是P450 2D6中间代谢者的一个简单半定量决定因素。经过验证的简单药代动力学模型能够预测大多数儿科患者中已获批准药物托莫西汀及其主要代谢物的稳态血浆浓度。药品说明书建议谨慎增加剂量，尤其是对于代谢不良者；然而，目前不存在确定P450 2D6表型的简单方法。即时尿样/血浆样本中4-羟基托莫西汀和去甲托莫西汀的相对较窄范围比值可能是P450 2D6中间代谢者优化或确认正确剂量的一个简单半定量决定因素。
