Matthew Harwood – Certara

Transporter inhibition: modelling in-vitro Transwell Assays

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Beam Me Up, Scotty! Probing the Mechanisms of Transporter-mediated Drug Disposition

on Jul 27, 2018 8:00:08 AM

Over the last 15 years, the importance of drug transporters has become paramount for understanding drug absorption, distribution into tissues, and in particular, drug-drug interactions (DDIs). In vitro-in vivo extrapolation (IVIVE) is an approach to link in vitro systems to the human in vivo situation using algorithms and physiologically-based scaling factors. In this blog, I […]

Topics: PBPK Modeling & Simulation

What’s New in the Simcyp Simulator v17?

Watch this webinar with Nikunjkumar Patel, Oliver Hatley, and Matthew Harwood to learn how the latest updates in the Simcyp Simulator v17 will help provide insights that support developing safer, more effective medications.

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Physiologically-based Pharmacokinetic (PBPK) Modeling to Explore the Potential Role of Cytochrome P450 3A Enzyme in Colonic Drug Metabolism—Oxybutynin: A Case Study

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Abundance & Relative Segmental Expression of Intestinal Transporters in Caucasians: A Meta-analysis

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In Vitro-In Vivo Extrapolation of Intestinal Transporter Activity Using an Absolute Transporter Abundance Approach Within a PBPK Framework

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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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Establishing the Colonic Mean Residence Time for Different Physical Drug Entities in Caucasians: A Meta-analysis

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

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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 […]

Topics: PBPK Modeling & Simulation

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

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

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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

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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