Matthew Harwood – Certara

Establishing the Relationship between Relative mRNA Expression and Protein Abundance for Seven Transporters in Human Small Intestine: A Pilot Study

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Incorporation of an Electrochemical Driving Force for the Renal Transport of Metformin by OCT in a Physiologically-based Pharmacokinetic Model of the Interaction between Metformin and Cimetidine

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Abundance of Hepatic Transporters in Caucasians: A Meta-analysis

The aim of this study was to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation (IVIVE) within a physiologically-based pharmacokinetic modeling framework. A meta-analysis was performed whereby abundance measurements, sample preparation method and donor demography were collated from literature. In order to define values for a healthy Caucasian population, […]

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Metformin and Cimetidine: Physiologically-based Pharmacokinetic Modeling to Investigate Transporter Mediated Drug–drug Interactions

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Comparison of the “well-stirred” gut and the “Q_Gut” models for predicting intestinal first-pass metabolism

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Prediction of Vss and Tissue Concentration-Time Profiles for Four Benzodiazepines Using Physicochemical, in vitro and Experimental Data in Rat using a Mechanistic PBPK Model

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Breast Cancer Resistance Protein, but not mRNA Expression Correlates with Estrone-3-Sulfate Bi-directional Transport Activity

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Laboratory differences in relative expression factors generated for intestinal P-glycoprotein and Breast Cancer Resistance Protein: Relevance to in vitro-in vivo extrapolation

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Towards gut drug transporter quantication with quantitative proteomics method QconCAT

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A Cross-Laboratory Comparison of Caco-2 and Human Intestinal Drug Transporter Protein Abundances

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Lost in Centrifugation! Accounting for Transporter Protein Losses in Quantitative Targeted Absolute Proteomics (QTAP)

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Prediction of Diclofenac Pharmacokinetics using Early Drug Discovery In Vitro Data in a Mechanistic Dog Physiologically-based Pharmacokinetic Model – ‘Simcyp Dog’

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Challenges in the modeling of bidirectional transport experiments

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Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates with Estron e-3-Sulfate Transport in Caco-2

Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression […]

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The Next Horizons in Predicting Drug-drug Interactions

Posted by Matthew Harwood

on Mar 23, 2016 1:08:47 PM

Physiologically-based pharmacokinetic (PBPK) modeling has arrived in prime time. This quantitative mechanistic framework, combining physiology with drug information and clinical trial design, has become an integral part of drug discovery and development. PBPK has also gained currency within industry and regulatory agencies. Its applications are numerous, including simulation of pre-clinical, healthy volunteer and special population […]

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Topics: PBPK Modeling & Simulation

In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II—The Impact of Cross-laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatography-tandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REFiP-gp) and BCRP (REFiBCRP), […]

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In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part I—A Cross-laboratory Comparison of Transporter-protein Abundances and Relative Expression Factors in Human Intestine and Caco-2 Cells

Over the last 5 years the quantification of transporter-protein absolute abundances has dramatically increased in parallel to the expanded use of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetics (PBPK)-linked models, for decision-making in pharmaceutical company drug development pipelines and regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if the large range of reported variability is founded […]

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Application of an LC-MS/MS Method for the Simultaneous Quantification of Human Intestinal Transporter Proteins Absolute Abundance Using a QconCAT Technique

Transporter proteins expressed in the gastrointestinal tract play a major role in the oral absorption of some drugs, and their involvement may lead to drug-drug interaction (DDI) susceptibility when given in combination with drugs known to inhibit gut wall transporters. Anticipating such liabilities and predicting the magnitude of the impact of transporter proteins on oral drug absorption and DDIs requires quantification of […]

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Lost in Centrifugation: Accounting for Transporter Protein Losses in Quantitative Targeted Absolute Proteomics

In drug development, considerable efforts are made to extrapolate from in vitro and preclinical findings to predict human drug disposition by using in vitro-in vivo extrapolation (IVIVE) approaches. Use of IVIVE strategies linked with physiologically based pharmacokinetic (PBPK) modeling is widespread, and regulatory agencies are accepting and occasionally requesting model analysis to support licensing submissions. […]

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Absolute Abundance and Function of Intestinal Drug Transporters: A Prerequisite for Fully Mechanistic In Vitro-In Vivo Extrapolation of Oral Drug Absorption

The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we […]

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