Development and Clinical Validation of Model-Informed Precision Dosing for Everolimus in Liver Transplant Recipients.

IF 4.9 Q1 CHEMISTRY, MEDICINAL ACS Pharmacology and Translational Science Pub Date : 2024-12-12 eCollection Date: 2025-01-10 DOI:10.1021/acsptsci.4c00581

Jeayoon Lee, In-Wha Kim, Suk Kyun Hong, Nayoung Han, Kyung-Suk Suh, Jung Mi Oh

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Abstract

Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/F: 15.0 ± 0.5 L/h), and apparent volume of distribution (V_d/F: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed "dosE" web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.

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依维莫司在肝移植受者中精确给药模型的开发和临床验证。

依维莫司由于患者之间和患者体内的药代动力学变异性，呈现出显著的剂量挑战。本研究旨在开发和验证依维莫司在肝移植受者中的精确给药策略。该给药策略最初采用回顾性数据，采用非线性混合效应建模。该模型包括易于测量的协变量、体表面积、白蛋白和他克莫司谷浓度。该给药策略随后在一项前瞻性试验中得到验证，根据协变量，建议每12小时给药1至1.75 mg。对于有下体表面积和白蛋白的患者，建议降低剂量，并根据他克莫司谷浓度进行调整。估计的药代动力学参数（典型值±标准误差）、表观清除率（CL/F: 15.0±0.5 L/h）和表观分布容积（Vd/F: 862±79.3 L）使用来自20例患者的前瞻性临床数据进行改进，减少了个体间的差异。本研究成功建立并验证了依维莫司的群体药代动力学模型。开发的“dosE”网络平台将我们的药代动力学模型转化为医疗保健提供者的实用工具，举例说明了药物研究在临床实践中的应用，并有可能改善肝移植的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.