Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models,Clinical Pharmacokinetics

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Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-06-14 , DOI: 10.1007/s40262-022-01132-3
Mattia Berton _{1,

2} , Sara Bettonte _{1,

2} , Felix Stader ₃ , Manuel Battegay _{1,

2} , Catia Marzolini _{1,

2}

Affiliation

Background

Obesity is associated with physiological changes that can affect drug pharmacokinetics. Obese individuals are underrepresented in clinical trials, leading to a lack of evidence-based dosing recommendations for many drugs. Physiologically based pharmacokinetic (PBPK) modelling can overcome this limitation but necessitates a detailed description of the population characteristics under investigation.

Objective

The purpose of this study was to develop and verify a repository of the current anatomical, physiological, and biological data of obese individuals, including population variability, to inform a PBPK framework.

Methods

A systematic literature search was performed to collate anatomical, physiological, and biological parameters for obese individuals. Multiple regression analyses were used to derive mathematical equations describing the continuous effect of body mass index (BMI) within the range 18.5–60 kg/m² on system parameters.

Results

In total, 209 studies were included in the database. The literature reported mostly BMI-related changes in organ weight, whereas data on blood flow and biological parameters (i.e. enzyme abundance) were sparse, and hence physiologically plausible assumptions were made when needed. The developed obese population was implemented in Matlab^® and the predicted system parameters obtained from 1000 virtual individuals were in agreement with observed data from an independent validation obese population. Our analysis indicates that a threefold increase in BMI, from 20 to 60 kg/m², leads to an increase in cardiac output (50%), liver weight (100%), kidney weight (60%), both the kidney and liver absolute blood flows (50%), and in total adipose blood flow (160%).

Conclusion

The developed repository provides an updated description of a population with a BMI from 18.5 to 60 kg/m² using continuous physiological changes and their variability for each system parameter. It is a tool that can be implemented in PBPK models to simulate drug pharmacokinetics in obese individuals.

中文翻译：

描述肥胖人群解剖学、生理学和生物学变化的知识库，为基于生理学的药代动力学模型提供信息

背景

肥胖与可影响药物药代动力学的生理变化有关。肥胖个体在临床试验中的代表性不足，导致许多药物缺乏基于证据的剂量建议。基于生理的药代动力学 (PBPK) 建模可以克服这一限制，但需要详细描述正在调查的人群特征。

客观的

本研究的目的是开发和验证肥胖个体当前解剖学、生理学和生物学数据（包括人口变异性）的存储库，为 PBPK 框架提供信息。

方法

进行了系统的文献检索，以整理肥胖个体的解剖学、生理学和生物学参数。多元回归分析用于推导描述体重指数（BMI）在 18.5-60 kg/m ²范围内对系统参数的连续影响的数学方程。

结果

总共有 209 项研究被纳入数据库。文献报道的主要是 BMI 相关的器官重量变化，而关于血流和生物参数（即酶丰度）的数据很少，因此在需要时做出了生理上合理的假设。开发的肥胖人群在 Matlab ^®中实施，从 1000 个虚拟个体获得的预测系统参数与来自独立验证肥胖人群的观察数据一致。我们的分析表明，BMI 增加三倍，从 20 到 60 kg/m ²，导致心输出量 (50%)、肝脏重量 (100%)、肾脏重量 (60%)、肾脏和肝脏的增加绝对血流量（50%）和总脂肪血流量（160%）。