Webinar Series

Comparison Between the Final US FDA, Japan PMDA, and EMA In Vitro DDI Guidance Documents: Are We Finally Harmonized?

Aired:  21 April 2020

Presenter: Brian Ogilvie, Ph.D., SEKISUI XenoTech Vice President of Scientific Consulting
In January, the FDA published its final guidance for industry on in vitro drug-drug interaction (DDI) studies. Dr. Ogilvie will offer his expert perspectives on major changes to the document, whether they will impact your drug development strategy, and with over 25 years of experience on the subject, what SEKISUI XenoTech’s strategy is to address potential development challenges presented by the final guidance. He will also compare it with the current EMA and PMDA in vitro guidance documents and discuss how to harmonize your drug development strategies to meet the expectations of all three.

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
  • A comparison of each agency’s guidance documents
  • A comparison of the equations and cutoff values
  • A comparison of experimental details
  • How to design studies to meet the expectations of each agency’s guidance documents
  • Impacts on in vitro DDI study design and interpretation
  • How SEKISUI XenoTech approaches developing effective strategies to ensure drug development programs are not delayed
  • Why good science is always a trump card

Approved registrants will receive a link to the recording, slides and comparison poster.

In Vitro ADME & Drug-Drug Interaction Considerations for Toxicologists

Aired:  17 April 2020

Presenter: Pallavi Limaye, Ph.D., SEKISUI XenoTech Director of Scientific Consulting
Originally scheduled to be presented at the canceled Society of Toxicology (SOT) 59th Annual Meeting & ToxExpo, our experts are bringing the tradeshow to you! Dr. Limaye will be discussing the intersection of ADME and toxicology in this webinar, followed by a live Q&A to address audience questions and comments.

In vitro ADME and drug-drug interaction (DDI) investigations are early activities in the drug development process that are critical for framing downstream decision making. This webinar will provide insights at a high-level related to regulatory drivers, investigatory objectives, and practical concerns for such studies that are relevant to interested general toxicologists. Participants will gain insight as to the critical need and utility for in vitro ADME and DDI investigations as related to drug development. Regulatory expectations will be reviewed as will points of particular interest for enabling successful achievement of investigatory goals.

Key concepts discussed in this webinar will include:
  • Why run these studies?
  • Predominant types of in vitro ADME & Drug-Drug Interaction (DDI) studies
  • When to conduct these studies
  • Areas of concern: Proper design & interpretation
  • And other highlights and information...

Register to attend on Friday, April 17th at:
10am EDT / 3pm CET
2pm EDT / 11am PDT
or to watch on-demand after the event

The Basics of In Vitro Xenobiotic Metabolism and Drug-Drug Interaction Investigations: Applicability to All Xenobiotics

Aired:  03 April 2020

Since SOT's 59th Annual Meeting and ToxExpo has been canceled due to COVID-19 concerns, we are bringing the tradeshow to you! SOT is hosting this course virtually on April 3rd from 12-2:30pm CDT. Our VP of Consulting, Dr. Brian Ogilvie, will be conducting the workshop alongside our founder, Andrew Parkinson, and an excellent list of presenters including:

  • Introductory Remarks on Xenobiotic Metabolism and Course Overview - Andrew Parkinson, XPD Consulting
  • The Basics of In Vitro CYP Inhibition Studies for Regulatory Submission and Risk Assessment - Brian Ogilvie, SEKISUI XenoTech
  • The Basics of In Vitro CYP Induction Studies for Regulatory Submission - Diane Ramsden, Alnylam Pharmaceuticals
  • In Vitro Reaction Phenotyping and the Toxicological Burden of Reactive Metabolites - Jed Lampe, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
  • Xenobiotic Transporter Studies for Regulatory Submission - Caroline Lee, Arena Pharmaceuticals
  • The Science of Drug Interactions Is Applicable to All Xenobiotics - Andrew Parkinson, XPD Consulting

If you cannot attend, a recording of the virtual course will become available to registrants on SOT's website approximately 1 week after the event. The course number for the workshop is AM07.

FAQ: Tips & Tricks for Working with Plateable Hepatocytes

Aired:  24 February 2020

Presenter: Halee McElhaney, SEKISUI XenoTech Team Lead, Quality Control

In the latest installment of ADME 101, one of our hepatocyte experts answers frequently asked questions about plateable hepatocytes, discusses common reasons why hepatocyte plating fails and demonstrates helpful techniques that will improve the performance of your plated hepatocytes in your in vitro assays. Topics include:

  • What are plateable hepatocytes used for?
  • What do we consider to be an attaching lot?
  • How do I choose which species to use?
  • How do I know what concentration is best for seeding?
  • What’s the difference between CryostaX and traditional hepatocytes?
  • How crucial is accurate cell count?
  • How long can my cells sit before I plate them?
  • Why do I have to wait until the next day to overlay rat hepatocytes?
  • My 96 wells aren’t working; what am I doing wrong?

To learn more, please review our hepatocyte thawing and plating protocol and watch our demo videos.

About the presenter: Halee McElhaney joined SEKISUI XenoTech in 2013 and is now one of our primary hepatocyte experts (pun intended). She has been on both sides of hepatocyte production. She started performing animal perfusions and processing tissue. Now she cultures hepatocytes for both in-house characterization and customers, provides quality control for all hepatocyte lots, troubleshoots in-house and client issues, and processes and interprets data. She also performs R&D and provides training for our team of Product Specialists.

ADME 101: Metabolite ID & Characterization Studies FAQ

Aired:  17 February 2020

Presenter: Mark Horrigan, SEKISUI XenoTech Principal Scientist, Program Oversight

In this short, information-packed ADME 101 video, one of our study directors discusses the main frequently asked questions that we receive about metabolite identification and characterization studies. Major topics of the presentation include:

About the presenter: Mark Horrigan joined SEKISUI XenoTech in 2005 as a Senior Mass Spectrometry Specialist and Qualitative Analysis group leader. Since then he has served as a Principal Scientist in the Drug Metabolism and Program Oversight Departments.

Drug Metabolism Related Safety Considerations in Drug Development

Aired:  05 December 2019

Presenter: Larry Wienkers, Ph.D., Sekisui XenoTech Consultant

With the close of our 2019 Drug Metabolism Updates Seminar Series, Dr. Wienkers presented his primary keynote topic as a webinar for all of those who could not attend one of our seminar events.

Approximately 30 years ago, sub-optimal DMPK properties were recognized as the primary contributor to the failure (~40%) of potential new therapies in early clinical trials. This observation precipitated a renaissance period across the discipline which served to align DMPK efforts within discovery to assist in selecting optimal drug candidates to advance to clinical testing. As a consequence, the failure rate for NCEs due to poor DMPK attributes is currently below 5%. While the success of DMPK groups to resolve issues is impressive, there is still a critical need to understand the activity and safety implications of key drug metabolites as part of the overall evaluation of the NCE.

This overview touches upon strategies for building phase appropriate packages for metabolites to account for pharmacological activity, potential drug interaction and associated metabolism-dependent drug safety concerns.

Watch the recording or register to download the slides:

Are in vitro metabolism and DDI studies critical for an IND?

Aired:  04 November 2019

Presenter: Greg Loewen, Director of Technical Support at SEKISUI XenoTech

Continuing our ADME 101 presentation series assisting researchers and industry professionals with navigating ADME, DMPK, and DDI within the complex landscape of drug development, Greg Loewen presented on whether in-vitro metabolism and drug-drug interaction (DDI) studies are critical for an IND at the 2019 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, PharmSci 360, in San Antonio, TX.

Drug metabolism and DDI studies often take a back seat to toxicity studies when preparing for an IND. Cross species metabolite identification and plasma protein binding are typically considered sufficient for an IND. However, benefits to drug development efficiency and expense along with modern regulatory expectations are causing many to look deeper earlier.

Metabolism studies can help bridge in vivo data to clinical outcomes. Furthermore, recent guidance documents from regulatory bodies indicate that DDI studies should be done before clinical studies. Lastly, when is the appropriate time to conduct ADME studies in pre-clinical species?

ADME 101: DMPK and ADME in Drug Development

Aired:  16 October 2019

Presenter: Joanna Barbara, Ph.D., Vice President of Scientific Operations at SEKISUI XenoTech

We are pleased to present SEKISUI XenoTech’s first ADME 101 series webinar, Acronyms Abound: DMPK and ADME in Drug Development. ADME 101 is a comprehensive new collection of educational short videos to serve as a resource for researchers and industry professionals to navigate ADME, DMPK, and DDI within the complex landscape of drug development. As we continue to update and add to our repository of resources, we welcome questions and requests for topics our experts may address in future presentations. Please use our online forms to request a topic or get in touch with our team.

Key concepts discussed in this webinar will include:

  • The overarching aim of therapeutic drug development
    • DMPK – Drug metabolism and pharmacokinetics
    • Based on ADME properties
  • Relationship to Drug-Drug Interactions (DDI)
  • ADME properties...

Transporters of Emerging Importance in Drug Development: Beyond the Guidance Documents

Aired:  16 May 2019

Presenter: Brian Ogilvie, Ph.D., Sekisui XenoTech Vice President of Scientific Consulting

In October, 2017, the US 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. For investigation of the transporter inhibition or substrate potential of drug candidates, the FDA updated the prior in vitro list (i.e., P-gp, BCRP, OATP1B1 & 3, OAT1 & 3, and OCT2) to include MATE1 and MATE2-K. Notably absent from this list was OCT1, which is a highly polymorphic hepatic uptake transporter, included in the European Medicines Agency (EMA) Final DDI Guideline from 2013.

In 2018 the International Transporter Consortium published a paper recommending prospective evaluation of OCT1. Other transporters covered by the ITC, including OATP2B1 and OAT2, along with the evidence for their emerging importance will also be highlighted. Finally, consideration of other transporters important for drug distribution during atypical routes of administration will be discussed (e.g., nasal and ophthalmic).

Key concepts discussed in this webinar will include:
  • 2017 FDA guidance update
  • In vitro transporter additions and eliminations in updated guidance
  • OCT1 evaluation in FDA versus EMA official documents
  • Impacts of polymorphisms
  • 2018 ITC paper discussing OCT1
  • Other important transporters covered by ITC paper
  • Extended Clearance Classification System (ECCS) prediction of rate-determining step in Absorption, Distribution, Clearance & Elimination (ADCE)
  • Atypical routes of administration

In Vitro Induction Studies: Elements of Design and Important Considerations in Data Analysis

Aired:  24 April 2019

Presenter: Joanna Barbara, Ph.D., Vice President of Scientific Operations at Sekisui XenoTech

When evaluating drug-drug interaction (DDI) risk of an investigational drug, a battery of studies is needed to investigate victim/perpetrator potential. One of these comprises evaluation of the potential of a new therapy to induce drug-metabolizing enzymes, which can impact clearance of concomitantly administered drugs. The team at Sekisui XenoTech has built a reputation of dedicating high quality resources and specialists to conduct such studies with scientific rigor.

In this webinar, Dr. Joanna Barbara will address frequently asked questions from sponsors seeking induction studies and elaborate on some recommendations we give to achieve successful regulatory submission. Points of discussions will include an overview of enzyme induction studies and critical considerations in design, from determination of supporting data to conclusive interpretation.

Key concepts discussed in this webinar will include:
  • Standard study considerations
  • FDA guidance requirements
  • Required endpoints for IND submission
  • 3A induction and associated challenges
  • Next-step recommendations

In Vitro Evaluation of Immunomodulating Drugs as Perpetrators of Drug Interactions

Aired:  20 February 2019

Presenter: Dr. Maciej Czerwinski, Sekisui XenoTech Director of Consulting

On October 15th, 2018, Sekisui XenoTech presented on "In Vitro Direct and Cytokine-Mediated Effects of Therapeutic Peptides and other Biologics on CYP Enzymes" at the Peptide ADME Discussion Group Workshop in Gothenburg, Sweden. Following subsequent requests for a follow-up webinar, Dr. Czerwinski will be presenting on the following subjects...

Key concepts discussed in this webinar will include:

Understanding P-gp & BCRP Inhibition Assay Design & Outcomes

Aired:  11 December 2018

Presenter: Andrea Wolff, Sekisui XenoTech Director of Services Logistics

In vitro drug transporter inhibition studies are recognized for their importance due to the major role transporters play in absorption, distribution and excretion of compounds, and the toxicological and pharmacological consequences of transporter-mediated drug-drug interactions (DDI). P-gp and BCRP transporters limit intestinal absorption and blood-brain barrier penetration, and facilitate excretion into bile and urine.

Andrea Wolff, Sekisui XenoTech Director of Services Logistics, recently provided a webinar to the SimCyp transporter discussion group on P-gp and BCRP Inhibition. For those who did not have the opportunity to hear her presentation, we hosted a follow-up webinar on Dec. 11th.

Key concepts discussed in this webinar will include:
  • Description of the in vitro test systems used to evaluate P-gp and BCRP inhibition at Sekisui XenoTech and the advantages/disadvantages of these assays
  • Description of the test system qualification process that takes places prior to offering these assays in definitive studies
  • Comparison of IC50 values obtained from the different test systems
  • Comparison of IC50 and Ki values determined with the vesicle test system
  • How IC50 and Ki values are used to evaluate clinical relevance

CryostaX Pellets: Improving hepatocyte pooling, activity and lab efficiency

Aired:  27 September 2018

Presenter:  Chris Bohl, Ph.D., Global Technical Support Manager

CryostaX® hepatocytes are created using a patented process that produces unique single-donor cell pellets. This format allows for distinct benefits to hepatocyte performance, efficiency in the lab, and test system design, precipitating the potential discontinuation of cryopreserved hepatocytes prepared from traditional methods. This webinar will discuss the technology, its optimal utilization and benefits...

Key concepts discussed in this webinar will include:
  • How single-freeze hepatocyte pellets preserve higher metabolic activity, longer
  • The benefits of skipping the thaw step
  • Pellet pooling versatility (demographics for human pools; larger rodent lot sizes)
  • Patented cryopreservation technology overview

About CryostaX:
CryostaX® patented hepatocyte technology makes using cryopreserved hepatocytes easier, more robust, and more efficient. Easier because you no longer need to thaw the vial of hepatocytes in a traditional water bath. Simply pour loose pellets into the thawing medium and spin. Higher metabolic activity pools because CryostaX technology allow the creation of fully customizable pools that have undergone only a single cryopreservation step, leading to less cryoinjury. More efficiency in the hood/bench because hepatocyte thaw variability is decreased and you are able to customize pools with specific demographics for your work. CryostaX hepatocytes come in all commonly used hepatocyte formats, are customizable (at no additional cost) for assured minimal yield per individual donor vial, and feature fast turnaround (in your hands in approx. 3-4 business days).

Challenges & Solutions In Today’s In Vitro Transporter Research Landscape

Aired:  20 June 2018

Presenter: Joanna Barbara, Ph.D., Sekisui XenoTech Vice President of Scientific Operations

Key concepts discussed in this webinar included:
  • Ramifications of recent FDA in vitro DDI guidance changes to transporter study designs
  • Challenges from diverse compounds in otherwise straightforward assays
  • Solutions to problems associated with specific compound characteristics
  • Case studies of problematic observations or data and the creative methods of troubleshooting applied

In vitro drug transporter inhibition and substrate potential assays as well as general cell permeability studies are performed at various stages of drug development to answer myriad questions. They can range from simple permeability screens to kinetic assessments in specialized cell systems using complex assay formats. 

Drug transporter assays are many and varied because numerous transporter proteins require evaluation, and study designs are usually based around the availability of an appropriate test system to study the transporter protein(s) in question. In general, experiments are conducted using polarized or transfected cell lines, hepatocytes or membrane vesicles. Each test system requires appropriate assay conditions and controls in order to generate useful data. 

Recent changes to the FDA in vitro DDI guidance document have emphasized the need for more considered transporter study designs to better inform in vivo expectations for drugs in development. The 2017 guidance explicitly recommends consideration of the impact of factors such as stability in the test system, non-specific binding to cells and experimental apparatus and other compound-specific characteristics in study conduct and data interpretation. Since assay designs are limited by individual test system assay needs, practically, this requires study designs to be augmented with careful monitoring and troubleshooting at assay and data interpretation stages when unexpected observations are made.

In this webinar, challenges associated with some diverse compounds in what should have been straightforward in vitro transporter assays will be examined. The discussion will focus on cell-based assays and the solutions applied to problems associated with specific compound characteristics, with a progressive analysis of increasingly complex case studies. Case studies will explore the problematic observations or data, creative methods of troubleshooting applied, and how we can learn from those experiences to better understand and address surprises in future transporter studies.

Patient-Derived Tumor Organoids for Personalized Medicine & Targeted Drug Discovery

Aired:  30 May 2018

Presenter: Motoki Takagi, Ph.D., Professor, Medical-industrial Translational Research Center, Fukushima Medical University

Patient-derived tumor organoids (PDOs) are cell aggregates produced by in vitro cell cultures of tumor tissue resected from patients. It is thought that PDOs better represent characteristics of tumor tissues in human body than ordinary cell lines. Therefore, they are considered as a more effective tool for the elucidation of cancer mechanisms and evaluation of anti-cancer agents. During the Fukushima Translational Research project*, PDOs were determined to be more similar to clinical tumor samples than ordinary cell lines in terms of gene expression profiling and thusly were coined as Fukushima PDOs (F-PDOs). This webinar is designed to introduce F-PDOs and present their features as well as the evaluation results of anti-cancer agents using F-PDOs.  

Key concepts discussed in this webinar will include:
  • Establishment and features of F-PDO
  • Difference between F-PDO and other PDOs
  • Anti-cancer drug evaluation using F-PDO
  • Advantages of F-PDO on PDX mouse development
*The Fukushima Translational Research project (Fukushima Project) was launched as part of the post-Great East Japan Earthquake reconstruction measures supported by the Ministry of Economy, Trade and Industry. The goal of the Fukushima project is to maximize the utilization of rare and trace biological samples by facilitating optimal:
  • Conversion into information
  • Sample processing and production of pathological models
  • Analytical technique development for ultratrace samples
  Registrants will be able to submit questions during registration as well as after viewing the webinar. Questions that weren't answered during the webinar will be responded to by email after the event. 

Comparison Between the US FDA, EU EMA and Japan PMDA In Vitro DDI Guidance Documents: Are We Close to Harmonization?

Aired:  19 December 2017

Co-Presenters: Brian Ogilvie, Ph.D., Sekisui XenoTech Vice President of Scientific Consulting, and Andrew Parkinson, Ph.D., XPD Consulting Chief Executive Officer
In September, the Japan PMDA revised its 2014 guideline and released it (only in Japanese) for comments. In October, the US 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. Drs. Andrew Parkinson, XPD Consulting, and Brian Ogilvie, Sekisui XenoTech, will offer their expert perspectives on major changes and differences between the two agencies’ in vitro guidance documents, and how to harmonize your drug development strategies to meet the expectations of both.

Key concepts discussed in this webinar will include:
  • An overview of the major changes and comparison of each agency’s guidance documents
  • A comparison of the equations and cutoff values
  • A comparison of experimental details
  • How to design studies to meet the expectations of each agency’s guidance documents

Register here to request access to the slides and recording of the webinar as well as the English-translated PMDA guideline document. Our convenient and informative reference poster is also available for download.

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

Request links to 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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