The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives

Abstract

Transporters play an important role in drug absorption, disposition, and drug action. The evaluation of drug transporters requires a comprehensive understanding of transporter biology and pharmacology. Physiologically based pharmacokinetic (PBPK) models may offer an integrative platform to quantitatively evaluate the role of drug transporters and its interplay with other drug disposition processes such as passive drug diffusion and elimination by metabolizing enzymes. To date, PBPK modeling and simulations integrating drug transporters lag behind that for drug-metabolizing enzymes. In addition, predictive performance of PBPK has not been well established for predicting the role of drug transporters in the pharmacokinetics of a drug. To enhance overall predictive performance of transporter-based PBPK models, it is necessary to have a detailed understanding of transporter biology for proper representation in the models and to have a quantitative understanding of the contribution of transporters in the absorption and metabolism of a drug. This article summarizes PBPK-based submissions evaluating the role of drug transporters to the Office of Clinical Pharmacology of the US Food and Drug Administration. Keywordstransporter, drug-drug interaction, physiologically based pharmacokinetic models, predictive performance Drug transporters play a critical role in drug absorption, disposition, and action.1,2 However, recognition of the importance of drug transporters and the implementation of a routine assessment in drug development lag behind the metabolizing enzymes. In addition, interpretation of the clinical significance of transporter data is more difficult than that for metabolizing enzymes for several reasons. First, the biology and pharmacology of certain transporters, especially the emerging transporters, are not fully understood. Second, major drug transporters are ubiquitously distributed in the body. For example, if a drug is tested as a substrate of P-glycoprotein (P-gp) in vitro, one needs to consider the role of P-gp in oral absorption through the intestine, distribution into the central nervous system, and elimination via active section in the liver and kidneys. Third, drug transporters are differentially localized in a variety of polarized cells, including enterocytes, hepatocytes, and proximal tubule cells. Within these cells, some transporters are located on the apical side, others on the basolateral side. These transporters often have distinctive functions (eg, efflux versus uptake) and regulate drug concentrations inside and outside the cells. Fourth, regulation of drug concentrations inside and outside the cells may be mediated simultaneously by transporters and passive diffusion processes. If a Pgp substrate has high passive permeability, it may still be effectively absorbed from intestinal lumen. Finally, transporter activities may affect a drug's contact with drug-metabolizing enzymes, a phenomenon known as enzyme-transporter interplay. Physiologically based pharmacokinetic (PBPK) models comb...

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