Investigation of simplified physiologically‐based pharmacokinetic models in rat and human

基于生理学的药代动力学模型 药代动力学 聚类分析 计算机科学 脂肪组织 计算生物学 生物系统 生物信息学 化学 生物 机器学习 生物化学
作者
Estelle Yau,Andrés Olivares‐Morales,Kayode Ogungbenro,Leon Aarons,Michael Gertz
出处
期刊:CPT: pharmacometrics & systems pharmacology [Nature Portfolio]
卷期号:12 (3): 333-345 被引量:3
标识
DOI:10.1002/psp4.12911
摘要

Whole-body physiologically-based pharmacokinetic (PBPK) models have many applications in drug research and development. It is often necessary to inform these models with animal or clinical data, updating model parameters, and making the model more predictive for future applications. This provides an opportunity and a challenge given the large number of parameters of such models. The aim of this work was to propose new mechanistic model structures with reduced complexity allowing for parameter optimization. These models were evaluated for their ability to estimate realistic values for unbound tissue to plasma partition coefficients (Kpu) and simulate observed pharmacokinetic (PK) data. Two approaches are presented: using either established kinetic lumping methods based on tissue time constants (drug-dependent) or a novel clustering analysis to identify tissues sharing common Kpu values or Kpu scalars based on similarities of tissue composition (drug-independent). PBPK models derived from these approaches were assessed using PK data of diazepam in rats and humans. Although the clustering analysis produced minor differences in tissue grouping depending on the method used, two larger groups of tissues emerged. One including the kidneys, liver, spleen, gut, heart, and lungs, and another including bone, brain, muscle, and pancreas whereas adipose and skin were generally considered distinct. Overall, a subdivision into four tissue groups appeared most physiologically relevant in terms of tissue composition. Several models were found to have similar abilities to describe diazepam i.v. data as empirical models. Comparability of estimated Kpus to experimental Kpu values for diazepam was one criterion for selecting the appropriate PK model structure.
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