Aldehyde Oxidase: What is Needed to Develop Robust Physiologically-Based Pharmacokinetic Models? | Dr. Sandhya Subash & Dr. Nihan Izat
This webinar will highlight the challenges and limitations for prediction of in vivo clearance for aldehyde oxidase (AO) substrates in human. Further, the consequences of poor prediction of AO clearance when developing physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be explained. Attendees will receive the latest research aimed at overcoming these challenges being performed by two academic centres of excellence.Joint webinar between Centre for Applied Pharmacokinetic Research (CAPKR; University of Manchester, UK) and Proteomics-based Research Initiative for Non-Cytochrome P450 Enzymes (PRINCE; Washington State University, US), two academic research consortia sponsored by pharmaceutical industry. Co-chairs: - Dr Daniel Scotcher (University of Manchester, UK) - Dr. Bhagwat Prasad (Washington State University, WA).
Aldehyde oxidase (AO) is a cytosolic molybdoflavoprotein enzyme, expressed mainly in liver, with wide range of substrates and capable of mediating oxidation and reduction metabolism. Following from progress towards reducing cytochrome P450 (CYP) liabilities of new drugs, AO has emerged as an increasingly common alternative metabolic pathway for drug metabolism. In particular, several drug development programs have failed due to poor prediction of in vivo drug clearance by AO; for example, toxicity and poor bioavailability in first-in-human trials. This webinar will explain the existing challenges of in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance of AO and dual AO CYP substrates from a variety of in vitro systems, and the latest research to resolve these. The development of physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be presented. In particular, the value and challenges of proteomics abundance data across tissues and population groups, and reverse translation of clinical data will be discussed. Relevance to clinical pharmacology including drug-drug interactions and dose adjustment in specific populations will be discussed.
- Dr Sandhya Subash (Washington State University, WA): "Key Factors Affecting Quality and Translatability of in vitro AO Mediated Metabolism Data"
- Dr Nihan Izat (University of Manchester, UK): "Current Perspectives on IVIVE of Aldehyde Oxidase and PBPK Modelling Strategies"