Using Expression Data for Quantification of Active Processes in Physiologically Based Pharmacokinetic Modeling

Abstract

ABSTRACT:Active processes involved in drug metabolization and distribution mediated by enzymes, transporters, or binding partners mostly occur simultaneously in various organs. However, a quantitative description of active processes is difficult because of limited experimental accessibility of tissue-specific protein activity in vivo. In this work, we present a novel approach to estimate in vivo activity of such enzymes or transporters that have an influence on drug pharmacokinetics. Tissue-specific mRNA expression is used as a surrogate for protein abundance and activity and is integrated into physiologically based pharmacokinetic (PBPK) models that already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: whole-genome expression microarrays from ArrayExpress, reverse transcription-polymerase chain reaction-derived gene expression estimates collected from the literature, and expressed sequence tags from UniGene. Expression data were preprocessed and stored in a customized database that was then used to build PBPK models for pravastatin in humans. These models represented drug uptake by organic anion-transporting polypeptide 1B1 and organic anion transporter 3, active efflux by multidrug resistance protein 2, and metabolization by sulfotransferases in liver, kidney, and/or intestine. Benchmarking of PBPK models based on gene expression data against alternative models with either a less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides accurate prediction of drug pharmacokinetics, integration of relative gene expression data in PBPK models offers the unique possibility to simultaneously investigate drug-drug interactions in all relevant organs because of the physiological representation of protein-mediated processes.

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

“…where ${\text{CL}}_{\mathrm{I}\mathrm{UGT}2\mathrm{B}7(\mathrm{child}\mathrm{g}\mathrm{liver})}^{\prime }$ is the scaled ${\text{CL}}_{\mathrm{normalI}}^{\prime }$ due to UGT2B7 per gram of liver, OSF UGT2B7 is the ontogeny scaling factor for UGT2B7 as a function of age,33 and ${\text{CL}}_{\mathrm{I}\mathrm{UGT}2\mathrm{B}7(\mathrm{adult}\mathrm{g}\mathrm{liver})}^{\prime }$ is the adult ${\text{CL}}_{\mathrm{normalI}}^{\prime }$ due to UGT2B7.…”

PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

“…Absorption, distribution, metabolism, and excretion‐relevant proteins reported to govern the PK of a drug, such as metabolizing enzymes, transporters, or binding partners, were implemented into the models and tested. Whenever available and in accordance with literature protein expression, the PK‐Sim expression database reverse transcription‐polymerase chain reaction (RT‐PCR) profiles8 were used to define the relative tissue distribution of these proteins. For parameters that could not be informed from ( in vitro ) experimental data, parameter identification based on plasma concentration‐time profiles was performed using a subset of the available clinical studies (training dataset) for optimization.…”

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“…Frequently, these data are not routinely available for regulatory purposes. However, examples of the successful application of PBTK models include the HMGCoA-reductase inhibitor pravastatin, bisphenol A or cumarin (Gundert-Remy et al 2013;Meyer et al 2012;Mielke et al 2011a;Mielke and Gundert-Remy 2012). Besides estimating the internal body exposure, PBTK was applied to address species differences and route-to-route extrapolation, respectively.…”

“…ref. Meyer et al 2012). Substance toxicity, including potential metabolites, would then be assessed in corresponding organomimetic cell culture systems.…”