Population pharmacokinetic analysis in children with different diseases treated with mycophenolate mofetil—Integrated analysis of clinical trials and real-world clinical data

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2024-11-21 DOI:10.1016/j.ejps.2024.106970
Jumpei Saito , Akimasa Yamatani , Miki Akabane , Mayumi Sako , Kandai Nozu , Kazumoto Iijima , Hidefumi Nakamura
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Abstract

Objectives

This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases.

Methods

To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model.

Results

A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95 % confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h–1. Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka.

Conclusions

An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population.

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使用霉酚酸酯治疗不同疾病儿童的群体药代动力学分析--临床试验和实际临床数据的综合分析。
研究目的本研究旨在建立霉酚酸(MPA)在不同疾病儿科患者中的群体药代动力学(PK)模型:为了建立PK模型,我们整合并分析了2013年2月至2022年5月在国家儿童健康与发展中心接受霉酚酸莫非替酯(MMF)治疗的不同疾病儿科患者的电子病历(EMR),以及2015年10月至2019年6月根据高级医疗护理B方案(JSKDC09研究)进行的儿科复杂性频繁复发类固醇依赖性肾病综合征MMF药代动力学研究的结果。非线性混合效应模型用于:1)建立跨疾病人群PK模型;2)通过事后贝叶斯方法估计PK参数(表观清除率CL/F和Q/F;表观分布容积Vc/F和Vp/F;吸收率常数Ka)。协变量分析包括患者背景、伴随药物和实验室数据。通过引导和预测校正进行视觉预测检查,以评估最终模型:共有249名患者的1495次测量数据被用于分析,其中包括68名肝移植后患者、65名肾病综合征患者、28名肾移植后患者、31名自身免疫性疾病患者(17名狼疮肾炎患者和14名其他胶原性疾病患者)、13名造血干细胞移植患者、5名来自EMR的其他患者以及39名来自JSKDC09研究的肾病综合征患者。具有一阶吸收率过程的二室模型最能解释 MPA 的 PK。观察到剂量与MPA暴露量之间存在非线性关系,并用模型的幂函数进行了描述。非肾移植患者和平均白蛋白水平的最终人群平均 PK 参数估计值(95% 置信区间)为:CL/F 15.2 (13.3, 18.0) L/h/70 kg、Vc/F 15.4 (14.4, 17.2) L、Vp/F 246.8 (159.1, 332.1) L、Q/F 7.0 (5.0, 9.0) L/h、Ka(不含质子泵抑制剂 [PPI])4.4 (2.4, 4.9) h-1。体重、疾病(肾移植后)和血清白蛋白水平是影响CL/F的重要协变量,血清白蛋白水平是影响Vc/F的重要协变量。PPIs的使用也会影响Ka:结论:针对以下情况的儿童建立了MPA的综合人群PK模型:实体器官移植后、HSCTx后、自身免疫性疾病和肾病综合征。估计参数和参数协变量与之前报道的相似。该模型有望为日本人在各种疾病中使用 MPA 提供有用的信息。
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来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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