On June 9, 2023, BioIVT hosted a symposium in Denmark featuring an array of BioIVT and industry experts discussing important topics relevant to ADME/Tox research. If you were unable to attend, a selection of the presentations is now available to view, including:
In Vitro Aspects of ICH M12, Industry and Technology
Speaker: Brian Ogilvie, PhD, Vice President of Scientific Consulting, BioIVT
Abstract: In June 2022, the ICH released the draft of its harmonized Drug Interaction Studies Guideline (M12). The guideline resulted from several meetings of the Expert Working Group since 2018 with the goal of harmonizing member regulatory agencies’ guidelines into one that will be used across all member countries. After review, the guideline will be adopted in 2024. This presentation will describe differences between current in vitro drug-drug interaction guidance from the relevant US FDA, EMA and PMDA guidance documents, and how to plan on meeting the ICH M12 guideline.
DDI Potential of Major Pharmaceutical Excipients on Transporters and Enzymes
Speaker: Mark Warren, PhD, Senior Director of Transporter Assay Services, BioIVT
Abstract: Excipients are “inactive” ingredients that are added to therapeutic drug products that are not intended to exert therapeutic effects by themselves. However, these excipients may inhibit intestinal transporters that can be responsible for enhancing or reducing the absorption of not only the drug that is administered along with the excipient, but also the absorption of co-medications that have never been tested with that excipient. Generic products may contain different excipients than the original branded medication, which may also contribute to unexpected drug-drug interactions. Numerous excipients were tested and shown to inhibit OATP2B1, an intestinal drug uptake transporter, as well as BCRP and P gp, intestinal drug efflux transporters.
Improving In Vivo Predictions from In Vitro Hepatocyte Models: Model Selection, Protein Effects, and Transporter Regulation
Speaker: Kenneth R. Brouwer, PhD, RPh, Vice President of Technology, ADME-Tox, BioIVT
Abstract: In both in vitro systems and in vivo, it is the unbound intracellular concentration (ICC) that is the driving force for processes that occur inside the hepatocyte. Achievement of an in vivo relevant ICC requires a polarized whole-cell system that integrates uptake into the hepatocyte, metabolism, and efflux (basolateral and canalicular) from the hepatocyte. Extensive protein binding can limit the uptake of many drugs, however for some drugs the estimation of intracellular concentration, and hepatic clearance cannot be correctly predicted based on the free (unbound) drug concentration. Additionally, studies have shown that transporters can be upregulated similar to metabolic proteins, resulting in increased uptake and/or efflux. Use of polarized whole-cell models and optimized culture conditions for in vitro systems may improve predictions of a drug’s in vivo properties and effects.