A physiologically based pharmacokinetic (PBPK) model of selegiline (SEL), and its metabolites, was developed in silico to evaluate the disposition differences between healthy and special populations. SEL is metabolized to methamphetamine (MAP) and desmethyl selegiline (DMS) by several CYP enzymes. CYP2D6 metabolizes the conversion of MAP to amphetamine (AMP), while CYP2B6 and CYP3A4 predominantly mediate the conversion of DMS to AMP. The overall prediction error in simulated PK, using the developed PBPK model, was within 0.5–1.5-fold after intravenous and transdermal dosing in healthy and elderly populations. Simulation results generated in the special populations demonstrated that a decrease in cardiac output is a potential covariate that affects the SEL exposure in renally impaired (RI) and hepatic impaired (HI) subjects. A decrease in CYP2D6 levels increased the systemic exposure of MAP. DMS exposure increased due to a reduction in the abundance of CYP2B6 and CYP3A4 in RI and HI subjects. In addition, an increase in the exposure of the primary metabolites decreased the exposure of AMP. No significant difference between the adult and adolescent populations, in terms of PK, were observed. The current PBPK model predictions indicate that subjects with HI or RI may require closer clinical monitoring to identify any untoward effects associated with the administration of transdermal SEL patch.

中文翻译：

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基于生理学的透皮司来吉兰及其代谢物的药代动力学模型，用于评估健康人群和特殊人群之间的处置差异

在计算机上开发了司来吉兰（SEL）及其代谢产物的基于生理的药代动力学（PBPK）模型，以评估健康人群和特殊人群之间的处置差异。SEL通过几种CYP酶代谢为甲基苯丙胺（MAP）和去甲基司来吉兰（DMS）。CYP2D6代谢MAP转化为苯丙胺（AMP），而CYP2B6和CYP3A4主要介导DMS转化为AMP。使用发达的PBPK模型，模拟PK的总体预测误差在健康和老年人群中静脉内和透皮给药后约为0.5-1.5倍。在特殊人群中产生的模拟结果表明，心输出量降低是可能影响肾功能不全（RI）和肝功能不全（HI）受试者SEL暴露的潜在协变量。CYP2D6水平的降低会增加MAP的全身暴露。由于RI和HI受试者中CYP2B6和CYP3A4含量的减少，DMS暴露增加。另外，主要代谢产物暴露的增加减少了AMP的暴露。就PK而言，未观察到成人和青少年之间的显着差异。当前的PBPK模型预测表明，患有HI或RI的受试者可能需要更密切的临床监测，以发现与施用透皮SEL贴片有关的任何不良影响。就PK而言，未观察到成人和青少年之间的显着差异。当前的PBPK模型预测表明，患有HI或RI的受试者可能需要更密切的临床监测，以发现与施用透皮SEL贴片有关的任何不良影响。就PK而言，未观察到成人和青少年之间的显着差异。当前的PBPK模型预测表明，患有HI或RI的受试者可能需要更密切的临床监测，以发现与施用透皮SEL贴片有关的任何不良影响。