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Applications of minimal physiologically-based pharmacokinetic models

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Abstract

Conventional mammillary models are frequently used for pharmacokinetic (PK) analysis when only blood or plasma data are available. Such models depend on the quality of the drug disposition data and have vague biological features. An alternative minimal-physiologically-based PK (minimal-PBPK) modeling approach is proposed which inherits and lumps major physiologic attributes from whole-body PBPK models. The body and model are represented as actual blood and tissue (usually total body weight) volumes, fractions (f d ) of cardiac output with Fick’s Law of Perfusion, tissue/blood partitioning (K p ), and systemic or intrinsic clearance. Analyzing only blood or plasma concentrations versus time, the minimal-PBPK models parsimoniously generate physiologically-relevant PK parameters which are more easily interpreted than those from mammillary models. The minimal-PBPK models were applied to four types of therapeutic agents and conditions. The models well captured the human PK profiles of 22 selected beta-lactam antibiotics allowing comparison of fitted and calculated K p values. Adding a classical hepatic compartment with hepatic blood flow allowed joint fitting of oral and intravenous (IV) data for four hepatic elimination drugs (dihydrocodeine, verapamil, repaglinide, midazolam) providing separate estimates of hepatic intrinsic clearance, non-hepatic clearance, and pre-hepatic bioavailability. The basic model was integrated with allometric scaling principles to simultaneously describe moxifloxacin PK in five species with common K p and f d values. A basic model assigning clearance to the tissue compartment well characterized plasma concentrations of six monoclonal antibodies in human subjects, providing good concordance of predictions with expected tissue kinetics. The proposed minimal-PBPK modeling approach offers an alternative and more rational basis for assessing PK than compartmental models.

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Acknowledgments

This research was supported by the National Institutes of Health Grant GM57980, the University at Buffalo—Pfizer Strategic Alliance, and the UB Center for Protein Therapeutics. Review of this manuscript by Drs. Sihem Ait-Oudhia, Peter Bonate, Wilhelm Huisinga, Wojciech Krzyzanski, Donald E. Mager, and Marilyn E. Morris is appreciated.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 404 Kapoor Hall, Buffalo, NY, 14214-8033, USA

    Yanguang Cao & William J. Jusko

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Correspondence to William J. Jusko.

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10928_2012_9280_MOESM1_ESM.docx

Supplementary material provides the ADAPT-5 code for operation of the models in Figure 2 and 3. Supplementary material 1 (DOCX 29 kb)

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Cao, Y., Jusko, W.J. Applications of minimal physiologically-based pharmacokinetic models. J Pharmacokinet Pharmacodyn 39, 711–723 (2012). https://doi.org/10.1007/s10928-012-9280-2

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