基于生理学的托吡酯在肝肾功能受损人群中的药代动力学建模和模拟,以及对药物间相互作用的考虑。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Shuqing Chen, Chaozhuang Shen, Yuchen Tian, Yuhe Peng, Jing Hu, Haitang Xie, Ping Yin
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引用次数: 0

摘要

托吡酯(TPM)是一种广谱抗癫痫药物(AED),常用于已获批准和未获批准的用途。由于托吡酯具有广泛的副作用,建议对特殊人群的临床用药进行常规监测。因此,进一步探索其药代动力学特性至关重要。我们从在线数据库中初步确定了 TPM 的物理化学特性,并在使用 PK-Sim 软件建立健康成人的 PBPK 模型时对其进行了进一步优化。然后将该模型外推至肾功能受损患者和肝功能受损患者。此外,还建立了一个药物-药物相互作用(DDI)模型,以模拟与卡马西平(CBZ)同时使用时的血浆 TPM 浓度。拟合优度法和平均折叠误差法用于比较预测值和观察值之间的差异,以评估 PBPK 模型的准确性。几乎所有的预测浓度都在相应观察浓度的两倍误差范围内。Cmax 和 AUC0-inf 的预测值与观察值的 AFE 比值均在 0.5 和 2 之间。建议将慢性肾脏病(CKD)3 期、4 期和 5 期患者的剂量分别降至健康成人剂量的 70%、50% 和 40%,将 Child-Pugh-B 和 Child-Pugh C 评分的肝功能受损患者的剂量分别降至约 70%和 35%。如果 TPM 与 CBZ 联合用药,根据模型模拟,建议将 TPM 剂量增加到单药剂量的 150%-175% 。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Physiologically based pharmacokinetic modeling and simulation of topiramate in populations with renal and hepatic impairment and considerations for drug-drug interactions.

Topiramate (TPM) is a broad-spectrum antiepileptic drug (AED) commonly prescribed for approved and off-label uses. Routine monitoring is suggested for clinical usage of TPM in special population due to its broad side effect profile. Therefore, it is crucial to further explore its pharmacokinetic characteristics. Physio-chemical properties of TPM were initially determined from online database and further optimized while establishing the PBPK model for healthy adults using the PK-Sim software. The model was then extrapolated to patients with renal impairment and patients who were hepatically impaired. A drug-drug interaction (DDI) model was also built to simulate plasma TPM concentrations while concomitantly used with carbamazepine (CBZ). The goodness-of-fit method and average fold error (AFE) method were used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. Almost all of the predicted concentration fell within twofold error range of corresponding observed concentrations. The AFE ratio of predicted to observed values of Cmax and AUC0-inf was all within 0.5 and 2. It is recommended that the doses be reduced to 70%, 50%, and 40% of the healthy adult dose for the chronic kidney disease (CKD) stage 3, stage 4, and stage 5 patients, respectively, and reduced to ~70%, and 35% for the Child-Pugh-B, and Child-Pugh C scored patient with hepatic impairment, respectively. If TPM is co-administered with CBZ, increasing TPM doses to 150%-175% of the monotherapy dose is recommended according to model simulation.

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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