Webinar Series

Essential Considerations on the New FDA In Vitro DDI Guidance (the What, the Why, and the Wow)

Aired:  21 November 2017

Presenter: Brian Ogilvie, Ph.D., Sekisui XenoTech Vice President of Scientific Consulting
 
In October, the FDA revised and split its 2012 draft guidance for industry on in vitro drug-drug interaction (DDI) studies, into one document for in vitro DDI studies, and another for clinical DDI studies. Dr. Brian Ogilvie will offer expert perspective on major changes to the in vitro guidance, whether they will impact your drug development strategy, and with more than two decades of experience in the area what Sekisui XenoTech’s strategy is to address potential development challenges presented by the draft.

Key concepts discussed in this webinar will include:
  • An overview of the major changes
  • Are these recommendations or requirements?
  • Views of the worldwide DDI guidance landscape
  • Impacts on in vitro DDI study design and interpretation
  • How Sekisui XenoTech approaches developing effective strategies to ensure drug development programs are not delayed
  • Considerations of whether to wait until the draft guidance is final, or to progress development of new drug candidates
  • Why good science is always a trump card

Register to view the slides and recording here.

Drug Metabolizing Enzymes and Transporters in NASH

Aired:  15 February 2017

Research Application of Variants of Fatty Liver Disease (FLD) Tissues

Presented by Maciej Czerwinski, Ph.D., Sekisui XenoTech Director of Consulting

Sekisui XenoTech is committed to the support of research into human diseases, particularly of the liver. In the course of over twenty years of pharmacokinetic studies in human hepatocytes, we have accumulated normal and diseased tissues representing FLD with or without history of excessive alcohol consumption and steatohepatitis. In this webinar, characteristics of the FLD and the effects of the condition on drug metabolism and disposition will be outlined. Organ collection procedures, storage and characterization of the specimens, as well as features of donors with and without significant consumption of alcohol, T2 and T1DM and pediatric donors will be described.

Key concepts discussed:
  • Fatty liver disease – characterization and progression
  • Effects of fatty liver diseases on drug metabolism and transport

View Other Potential Upcoming Webinar Topics

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

Introduction to the BMO Kit: An Alternative Metabolite Production Tool

Aired:  03 December 2014

In recent years, the FDA guidance on metabolites in safety testing (MIST) has put pressure on pharmaceutical comopanies to investigate metabolites and their potential toxicity. In that context, Biomimetic Oxidation, aka BMO, has emerged as a serious alternative to microsomes or recombinant CYPs to produce testable quantities of metabolite. This method uses chemical catalysts to mimic phase I metabolism and can be easily scaled-up to produce metabolites in sufficient quantities to allow in vitro testing and structure elucidation. XenoTech will present a description of the technology and the BMO kit which has been designed by HepatoChem.

Key concepts discussed in this webinar include:

  • Biomimetic oxidation catalysis
  • Description of the BMO Kit protocol
  • Example of produced metabolites

Providing Consultative DMPK Solutions Bridging Drug Discovery and Development

Aired:  21 November 2013

XenoTech and XenoGesis work together to facilitate outsourced drug metabolism and pharmacokinetics (DMPK) studies from early stage drug discovery through development and beyond. Our partnership was developed to help mitigate the risk and cost associated with clinical failure. Efficacy and safety are now the leading causes of attrition and are linked to drug exposure in target and off-target tissues. While pharmacokinetics is no longer the leading cause of failure, a drug’s exposure is driven by its pharmacokinetic properties and ultimately remains critical for successful pharmacodynamics and safety. We will showcase the consultative basis of our DMPK CRO alliance and highlight our capabilities with real-life examples of our unique combination of expertise.

Key concepts discussed in this webinar will include:

  • Factors that may contribute to low quality leads and ways to overcome these problems
  • Case studies to illustrate how the XenoTech / XenoGesis alliance can positively impact drug development
  • Capabilities and expertise of each CRO

Aldehyde Oxidase: Why In Vitro Absolute Activity Doesn't Matter

Aired:  27 September 2013

Biotransformation by aldehyde oxidase (AO) is an important clearance mechanism for many drugs and drug candidates, with increasing importance in certain chemical spaces, and in some cases, such as zaleplon, AO metabolism leads to rapid in vivo clearance. Several publications have demonstrated a consistent under-prediction of in vivo human clearance from in vitro clearance data, which are typically conducted with human liver subcellular fractions, such as S9 or cytosol.  Zientek and colleagues (2010) described a rank order, or ‘yard-stick’ approach, to categorize known AO substrates into low, medium or high clearance categories based on in vitro data.  With this approach, drug candidates can be evaluated in vitro in S9 or cytosol and the predicted in vivo clearance can be qualitatively ranked from low- to high-clearance.  We will present data to show that because of the necessity to scale AO clearance with a rank-order approach, nearly all human liver S9 and cytosol lots (individual or pooled) can be utilized to predict in vivo AO clearance once threshold values are determined with appropriate probe drugs.

Key concepts discussed in this webinar include:

  • Factors that may contribute to the lot-to-lot availability of AO activity
  • Utility of the yardstick approach for categorizing in vivo AO clearance of candidate drugs
  • Evidence that nearly any lot of human liver S9 or cytosol can be used for this approach

Navigating the Transporter Wave of 2013: A Review of the Seven Recent ITC Publications on Drug Transporters

Aired:  08 August 2013

Seven papers were published by the International Transporter Consortium (ITC) in the July 2013 issue of Clinical Pharmacology and Therapeutics. The ITC is a group of preeminent scientists from industry, academia and regulatory agencies and these seven papers represent the most current information on the study of transporters to predict possible drug-drug interactions. XenoTech will present critical highlights from each of the papers, contrast to current thinking and comment on the effect these papers will have on the drug development process.

Key concepts discussed in the webinar include:

  • Emerging clinically relevant transporters
  • Clinically relevant transporter polymorphisms
  • Kinetic parameter estimation and translational modeling
  • Potential for drug-drug interactions and the blood brain barrier
  • In vitro methods for studying drug transporters
  • Decision trees - in vitro results that drive in vivo studies
  • Measurement, modeling and implications of intracellular drug concentrations

Exploring the Mechanism of CYP3A4 Inactivation by Lapatinib Through In Vitro Metabolite Char.

Aired:  06 March 2013

Metabolism-dependent inhibition of cytochrome P450 enzymes has the potential to cause clinically-relevant drug-drug interactions. Alkylamine drugs are known for their propensity to cause CYP inhibition by formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron of the enzyme. The secondary alkylamine drug lapatinib has been linked both to drug-induced liver injury and quasi-irreversible inhibition of CYP3A4. In the present study, in vitro techniques to probe reversibility of enzyme inactivation were combined with metabolite profiling by high-resolution liquid chromatography with accurate mass spectrometry to explore the mechanism of CYP3A4 inactivation associated with lapatinib metabolism.

Key concepts discussed in this webinar will include:

  • Insight into metabolism-dependent CYP inhibition by alkylamines
  • Utility of in vitro reversibility assays
  • Mechanism of CYP3A4 inactivation by the tyrosine kinase inhibitor lapatinib

Application of Hepatocytes for In Vitro Uptake Assays

Aired:  06 February 2013

This webinar provides a basic review of concepts applicable to a structure-based approach for the evaluation of hepatic uptake with in vitro hepatocyte experiments.

Key concepts discussed in this webinar will include:

  • Selection of appropriate in vitro study type and design based on predictions from a drug candidate's phys-chem properties
  • Description of the basic in vitro methodologies using hepatocytes, both suspension and plated, to evaluate drug uptake, namely whole-system versus medium loss, oil-spin method and uptake into plated cells
  • Discussion of the practical challenges associated with these experiments
  • Basic review on the estimation of active and passive uptake components from these in vitro hepatocyte experiments
  • Impact of phys-chem properties, active and passive uptake and metabolism on the estimation of free intracellular drug concentrations
  • Brief review of the prediction of in vivo hepatic clearance from in vitro uptake experiments and potential scaling techniques

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