On the Nature of Physiologically-Based Pharmacokinetic Models –A Priori or A Posteriori? Mechanistic or Empirical?

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• 作者：Ken Korzekwa ; Swati Nagar
• 关键词：KEY WORDSclearance ; PBPK ; tissue partitioning
• 刊名：Pharmaceutical Research
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：34
• 期：3
• 页码：529-534
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Pharmacology/Toxicology; Pharmacy; Biochemistry, general; Medical Law; Biomedical Engineering;
• 出版者：Springer US
• ISSN：1573-904X
• 卷排序：34

文摘

Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be “bottom up” as opposed to “top down”. Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone). Both “bottom up” and “top down” approaches can incorporate either empirical or mechanistic components. In this perspective, we discuss some of the methods and assumptions of current PBPK modeling approaches. Specifically, we discuss drug partitioning into phospholipids and neutral lipids, use of blood-plasma ratios to estimate basic drug tissue partitioning, and clearance of neutral and acidic drugs. Based on these discussions, we believe that current PBPK models are mechanistic but a posteriori and semi-empirical.