On the Nature of Physiologically-Based Pharmacokinetic Models –A Priori or A Posteriori? Mechanistic or Empirical?
Open accessAbstract
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.
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Cites
Partition coefficients and their uses
Leo, A., Hansch, C., & Elkins, D. R. (1971) · Chemical Reviews · doi:10.1021/cr60274a001 · Cited by 4,253 · see citing works
Robustness in the Strategy of Scientific Model Building.
Box, G. (1979) · Elsevier eBooks · doi:10.1016/b978-0-12-438150-6.50018-2 · Cited by 1,435 · see citing works
Rodgers, T., & Rowland, M. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20502 · Cited by 949 · see citing works
Rodgers, T., Leahy, D., & Rowland, M. (2005) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20322 · Cited by 776 · see citing works
The Contribution of Sialic Acid to the Surface Charge of the Erythrocyte
EYLAR, E. H., Madoff, M. A., Brody, O. V., et al. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)73972-6 · Cited by 703 · see citing works
Poulin, P., & Theil, F. (2002) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10005 · Cited by 568 · see citing works
Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes
Rodgers, T., & Rowland, M. (2007) · Pharmaceutical Research · doi:10.1007/s11095-006-9210-3 · Cited by 420 · see citing works
Lipid solubility and drug penetration of the blood brain barrier
Oldendorf, W. H. (1974) · Experimental Biology and Medicine · doi:10.3181/00379727-147-38444 · Cited by 373 · see citing works
Red Blood Cells: A Neglected Compartment in Pharmacokinetics and Pharmacodynamics
Hinderling, P. H. (1997) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01329-2 · Cited by 250 · see citing works
Linear free energy relations between partitioning solvent systems
Leo, A. J., & Hansch, C. H. (1971) · The Journal of Organic Chemistry · doi:10.1021/jo00810a023 · Cited by 145 · see citing works
PREDICTION OF IN VIVO DRUG DISPOSITION FROM IN VITRO DATA BASED ON PHYSIOLOGICAL PHARMACOKINETICS
Iwatsubo, T., Hirota, N., Ooie, T., SUZUKI, H., & Sugiyama, Y. (1996) · Biopharmaceutics & Drug Disposition · doi:10.1002/(sici)1099-081x(199605)17:4 · Cited by 139 · see citing works
Peyret, T., Poulin, P., & Krishnan, K. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.09.010 · Cited by 136 · see citing works
Poulin, P., & Krishnan, K. (1995) · Human & Experimental Toxicology · doi:10.1177/096032719501400307 · Cited by 126 · see citing works
Application of PBPK modelling in drug discovery and development at Pfizer
Jones, H. M., Dickins, M., Youdim, K. A., Gosset, J. R., Attkins, N. J., Hay, T. L., Gurrell, I. K., Logan, Y. R., Bungay, P. J., Jones, B., et al. (2011) · Xenobiotica · doi:10.3109/00498254.2011.627477 · Cited by 98 · see citing works
Modeling Kinetics of Subcellular Disposition of Chemicals
Baláž, Š. (2009) · Chemical Reviews · doi:10.1021/cr030440j · Cited by 82 · see citing works
Phosphatidylserine as a Determinant for the Tissue Distribution of Weakly Basic Drugs in Rats
Yata, N., Toyoda, T., Murakami, T., Nishiura, A., & Higashi, Y. (1990) · Pharmaceutical Research · doi:10.1023/a:1015935031933 · Cited by 78 · see citing works
Partition coefficients and the structure-activity relation of the anesthetic gases
Hansch, C. H., Vittoria, A., Silipo, C., et al. (1975) · Journal of Medicinal Chemistry · doi:10.1021/jm00240a002 · Cited by 77 · see citing works
Ye, M., Nagar, S., & Korzekwa, K. (2015) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1996 · Cited by 54 · see citing works
Self-citationNiimi, A. J. (1991) · Water Research · doi:10.1016/0043-1354(91)90182-p · Cited by 47 · see citing works
Poulin, P., & Haddad, S. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24676 · Cited by 45 · see citing works
Binding of propranolol and gentamicin to small unimellar phospholipid vesicles
Kubo, M., Gardner, M. F., & Hostetler, K. Y. (1986) · Biochemical Pharmacology · doi:10.1016/0006-2952(86)90662-3 · Cited by 42 · see citing works
Amiodarone Partitioning with Phospholipid Bilayers and Erythrocyte Membranes
Chatelainx, P., & Laruel, R. (1985) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600740720 · Cited by 40 · see citing works
Takegami, S., Kitamura, K., Kitade, T., et al. (2005) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.53.147 · Cited by 19 · see citing works
Structural Determinants of Drug Partitioning in Surrogates of Phosphatidylcholine Bilayer Strata
Lukáčová, V., Natesan, S., Peng, M., et al. (2013) · Molecular Pharmaceutics · doi:10.1021/mp400204y · Cited by 16 · see citing works
Hansch, C. H., Vittoria, A., Silipo, C., et al. (1975) · ChemInform · doi:10.1002/chin.197540416 · Cited by 15 · see citing works
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Research works printed but not linked: 1
- [15]Davies JT A quantitative kinetic theory of emulsion type, I. Physical chemistry of the emulsifying agent. In Gas/Liquid and Liquid/Liquid Interface Proceedings of the International Congress of Surface Activity 1957 426 438
Cited by
Sorted by citations
Miller, N. A., Reddy, M. B., Heikkinen, A. T., Lukacova, V., & Parrott, N. (2019) · Clinical Pharmacokinetics · doi:10.1007/s40262-019-00741-9 · Cited by 142 · see citing works
- Authors
- Korzekwa, K., & Nagar, S.
- Affiliations
- Temple University (US)
- Corresponding author
- Korzekwa, Ken
- Venue
- Pharmaceutical Research
- Published
- 2016-12-27
- Volume
- 34
- Issue
- 3
- Pages
- 529-534
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- PMC
- PMC5469509
- OpenAlex
- W2562277823
- Cited by
- 18
- References
- 25
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 2
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (1R01GM114369, 1R01GM104178)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- physiologically based pharmacokinetic modeling, bottom-up modeling, top-down modeling, drug partitioning, tissue partitioning, drug clearance, acidic drugs, tissue blood flow, partition coefficient
- MeSH terms
- Chemistry, Pharmaceutical, Pharmaceutical Preparations, Humans, Models, Biological, Pharmacokinetics, Phospholipids, Tissue Distribution, Molecular Structure
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