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Korzekwa K , Nagar S
On the Nature of Physiologically-Based Pharmacokinetic Models -A Priori or A Posteriori? Mechanistic or Empirical?
Pharm Res. 2017 Mar;34(3) :529-534
PMID: 28028770    PMCID: PMC5469509   
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Abstract
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.
Notes
1573-904x Korzekwa, Ken ORCID: http://orcid.org/0000-0002-7119-9200 Nagar, Swati R01 GM104178/GM/NIGMS NIH HHS/United States R01 GM114369/GM/NIGMS NIH HHS/United States Journal Article United States Pharm Res. 2017 Mar;34(3):529-534. doi: 10.1007/s11095-016-2089-8. Epub 2016 Dec 27.