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