Proteomics-Informed PBPK Modeling to Predict Systemic and Tissue Drug Concentrations in Rats

Majority of drugs fail in clinical trials due to limited efficacy or safety, partly because of the inability to measure drug concentrations in target tissues where efficacy or toxicity occurs. Moreover, translating preclinical data to humans is often challenging when a drug undergoes substantial metabolism and transport, given the differences in the abundance of drug-metabolizing enzyme and transporter (DMET) proteins. The recent bill to implement Food and Drug Administration (FDA) Modernization Act 2.0 advocates for alternative methods for testing drug efficacy and safety. Physiologically based pharmacokinetic (PBPK) modeling is a reliable alternative to predict tissue and systemic drug concentrations, utilizing in vitro laboratory assays, DMET protein abundance, and physiology. Regulatory agencies such as the FDA and European Medicines Agency, also encourage to use PBPK modeling to support the drug development lifecycle and regulatory decision-making. This webinar presents a quantitative map of clinically relevant DMET proteins in the liver and intestinal segments of rats using quantitative global (untargeted) and targeted proteomics approaches and its integration in PBPK modeling. The session showcases the successful application of proteomics informed PBPK modeling to reliably predict systemic and tissue concentrations of digoxin as a case study.