Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVID treatment and other diseases, there is an unmet need for thorough understanding of its pharmacokinetic in special populations, such as the elderly. We aimed to mechanistically describe amantadine pharmacokinetics in healthy subjects and shed some light on the differences in drug behavior between healthy volunteers (18–65 years) and an elderly/geriatric population (65–98 years) using PBPK modeling and simulation. The middle‐out PBPK model includes mechanistic description of drug renal elimination, specifically an organic cation transporter (OCT)2‐mediated electrogenic bidirectional transport (basolateral) and multidrug and toxic compound extrusion (MATE)1‐mediated efflux (apical). The model performance was verified against plasma and urine data reported after single and multiple dose administration in healthy volunteers and elderly patients from 18 independent studies. The ratios of predicted vs. observed maximal plasma concentration and area under the concentration–time curve values were within 1.25‐fold. The model illustrates that renal transporter activity is expected to decrease in healthy elderly compared to healthy volunteers, which is in line with literature proteomic data for OCT2. The model was applied to assess the potential of reaching toxicity‐related plasma concentrations in different age groups of geriatric subjects.

中文翻译：

---

PBPK 如何帮助了解旧药并告知老年人的剂量：金刚烷胺案例研究

尽管金刚烷胺已上市 55 年，但其药代动力学仍有几个未知方面，特别是与年龄、疾病或与金刚烷胺肾消除相关的相互作用等协变量的影响有关。由于金刚烷胺用于治疗帕金森病，并被认为是治疗新冠肺炎和其他疾病的潜在候选药物，因此对其在老年人等特殊人群中的药代动力学有透彻了解的需求尚未得到满足。我们的目的是从机制上描述金刚烷胺在健康受试者中的药代动力学，并使用 PBPK 建模和模拟阐明健康志愿者（18-65 岁）和老年人/老年群体（65-98 岁）之间药物行为的差异。中出 PBPK 模型包括药物肾脏消除的机制描述，特别是有机阳离子转运蛋白 (OCT)2 介导的生电双向转运（基底外侧）和多药物和有毒化合物挤出 (MATE)1 介导的外排（顶端）。该模型的性能根据来自 18 项独立研究的健康志愿者和老年患者单剂量和多剂量给药后报告的血浆和尿液数据进行了验证。预测与观察到的最大血浆浓度和浓度-时间曲线下面积值的比率在 1.25 倍以内。该模型表明，与健康志愿者相比，健康老年人的肾脏转运蛋白活性预计会降低，这与 OCT2 的文献蛋白质组数据一致。该模型用于评估不同年龄组老年受试者达到毒性相关血浆浓度的潜力。