Adverse Drug Interaction Risks in Genetically-Defined Subpopulations

Aired:  20 June 2016

Presenter:  Maciej Czerwinski, Ph.D., Director of Sekisui XenoTech Products R&D

Synopsis: An increased appreciation of the effects of genetic variability on the pharmacokinetic and pharmacodynamic properties of xenobiotics creates a need for specialized tools to evaluate new drugs from the pharmacogenomics perspective. Preclinical examination of drug metabolism with consideration of patient population diversity may reduce the risk of adverse effects upon first administration of a xenobiotic to humans and during further phases of drug testing and expansive use. An extensive polymorphism of drug metabolizing enzymes and drug transporters is well established. Human genetically-defined liver microsomes and most recently pooled cryopreserved hepatocytes constitute test systems for the pharmacogenetically-informed study of drug metabolism. Characterization of Sekisui XenoTech Geneknown™ hepatocytes and criteria applied for creating genetically-defined pools of cells are presented as part of the discussion.
Key concepts discussed in this webinar include:

  • Effects of drug metabolizing enzyme polymorphisms on drug disposition
  • Safety concerns associated with developing one dose for diverse patient population
  • Genetic basis for some of the polymorphisms of important drug metabolizing enzymes
  • Selecting the best test system to study the effects of specific genetic variants on drug metabolism
  • Donor selection for effective test pools

Evaluation of Ketoconazole and its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters

Aired:  13 April 2016

Publication Review: "Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin and Itraconazole on 13 Clinically-Relevant Drug Transporters"

​Presented by Lydia Vermeer, Ph.D., Senior Scientist, Drug Transport

Synopsis: Ketoconazole is known to be a strong CYP3A4/5 inhibitor, and until recently, was utilized in this role in clinical drug-drug interaction (DDI) studies. Unfortunately, ketoconazole has also demonstrated the ability to cause sporadic liver injury or adrenal insufficiency. Due to this, the FDA and EMA recently recommended the suspension of ketoconazole use in DDI studies and suggested the use of alternatives such as itraconazole or clarithromycin. While the effect on CYP3A4/5 function by these compounds is well established, the known effect on drug transporters is limited. The purpose of this study was to determine the inhibitory effects of ketoconazole, clarithromycin, ritonavir, itraconazole (and the itraconazole metabolites hydroxy-, keto-, andN-desalkyl-itraconazole) towards the drug transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3, and BSEP.

Key Concepts Discussed:
  • Ketoconazole use and background
  • Assay methodology and design
  • Inhibitory effects of ketoconazole and alternative compounds on drug transporters
  • Calculated IC50 values
  • Determination of potential for clinical DDI
  • Potential limitations of the study

Tritosomes and Lysosomes for Characterization of Biologic Drugs

Aired:  04 February 2016

"Investigation of freshly purified rat tritosomes and human hepatic lysosomes as an in vitro tool for characterization of biologic drugs"

Presented by Chris Bohl, Research Scientist, XenoTech Products R&D

Synopsis: The realization of new technologies and the development of targeted biopharmaceutical therapies have accelerated in the last decade with over 30 such compounds currently in clinical trials. With ongoing development and evaluation of strategies, such as antibody drug conjugates, to effectively deliver compounds to targeted cell populations through the endocytic-lysosomal pathway, the development and availability of novel reagents will become paramount. Isolated rat hepatic tritosomes and human hepatic lysosomes are in vitro systems that can be utilized to quickly and conveniently evaluate compound stability and guide development direction of biopharmaceutical candidates. In this study, subcellular isolation techniques combined with immunoblotting, protease arrays, and enzymatic activity assays were carried out to characterize isolated rat tritosomes and human liver lysosomes.

Key Concepts Discussed:
  • Isolation techniques and characterization
  • Insights into the differences between tritosomes and lysosomes
  • In vitro applications

View the poster: In vitro characterization of human liver lysosomes isolated from fresh tissue

Pre-register for the Upcoming Webinar: Updated Lysosome Data & Lysosomal Trapping