Sponsors and regulatory agencies routinely use physiologically-based pharmacokinetic (PBPK) modeling and simulation to assist in dose selection and inform drug labels. Certara’s PBPK platform, the Simcyp® Simulator, links in vitro data to in vivo absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic/pharmacodynamic (PK/PD) outcomes to explore potential clinical complexities prior to and during human studies and support decision-making in drug development.
Join this webinar with Peter Kilford, Mian Zhang, and Janak Wedagedera to learn how the latest updates in the Simcyp Simulator v19, guided by the Simcyp consortium members, will support developing safer, more effective medications faster. These enhancements include:
- Updates and Enhancements to the Simcyp® Substrate and Inhibitor Libraries: The Simcyp library currently includes over 75 fully verified substrate, inhibitor, and metabolite PBPK models that are used to support global regulatory submissions. Simulation of clinical drug-drug interactions (DDIs) is increasingly being used. Over 48 regulatory approvals have used Simcyp Simulator to provide label information on clinical DDIs potentials and dose adjustments. The Simcyp team are continually evaluating and updating the compound models. For V19 of the Simcyp Simulator, 29 compound files have been either developed, updated, or expanded to further enhance its use for drug development. The updates in V19 focused on key areas of development including addition of the Advanced Dissolution Absorption and Metabolism (ADAM) model for substrates to account for food effects, updates to compounds that are transported (renal and OATP), review of clearance and inhibition parameters, and improvement/expansion of the rifampicin induction model.
- Metabolite Back Conversion in Plasma and Tissues: Many compounds undergo reversible biotransformation, which can impact their pharmacokinetics, DDIs, and PD. Thus, it is crucial to be able to model parent-to-metabolite inter-conversion and to quantitatively predict its impact. Thus, the Simcyp Simulator V19 now enables modelling parent-to-metabolite inter-conversion simultaneously in the liver, gut enterocytes, kidney, and blood circulation. The inter-conversion can be mediated by multiple enzymes so that the impact of DDI and polymorphisms on inter-conversion can be evaluated quantitatively. In addition, flavin-containing monooxygenase pathways with an absolute abundance based scaling framework are also incorporated. These new features alongside the currently available functionalities enable modelling sophisticated behaviors of drug metabolites and allow predicting the impact of reversible biotransformation on PK, DDIs, and PD.
- Enhancements in Parameter Estimation and Sensitivity Analysis: Estimation of parameters with uncertainty within PBPK models is important for multiple reasons. Firstly, it’s needed to refine PBPK models and characterize the variability of exposure or responses to drugs within a population or an individual of interest. Furthermore, it is important to understand the sensitivity of various model outputs (e.g. AUC, Cmax, Tmax, PD response) to model input parameters. In this context, that helps constrain the parameter values to appropriate physiological ranges within the estimation methods and focus data collection on the important parameters. The Simcyp Simulator V19 provides tools and state-of-the-art methodologies for fitting PBPK models to observed data and for performing Global Sensitivity Analysis. In V19, its capability for both individual and population fitting is significantly expanded. This version now provides a collection of powerful tools for Global Sensitivity Analysis including the Morris Sobol and extended Sobol methods.
About Our Speakers
Janak Wedagedera is a Senior Research Scientist at Certara UK Limited’s Simcyp Division. He received his PhD in Mathematics from University of Wales- UK and postdoctoral training from University of Warwick – UK in Systems Immunology. After serving many years in academia as a Professor in Mathematics at the University of Ruhuna – Sri Lanka, a Visiting Professor at York University – Canada in the areas of Probability and Statistics, Disease Modelling and Systems Immunology, he joined the Simcyp team in 2013. Since then he has worked in and lead various projects in PBPK/PD Modeling, Nonlinear Optimization methods, statistical methodology, and numerical solutions via ODE solvers in a Population-PBPK context.
After receiving a BSc in Biochemistry with Toxicology, Peter completed his PhD at the University of Manchester in 2008. Peter joined the Certara, UK Simcyp Division in early 2019 to work in the science team focusing on further developments to the metabolism side of the Simcyp Simulator.
Mian Zhang is a Research Scientist at Certara UK Limited’s Simcyp Division. Mian received his PhD in DMPK from the China Pharmaceutical University. Prior to joining Simcyp, he spent his early career as a scientist in the Pharmaceutical Science Dept. at Hutchison Medi Pharma and a Senior Scientist in the DMPK Services Dept. at WuXi AppTec. Since joining Simcyp, he has led and contributed to various projects for the development and application of the Simulator for drug metabolism, transporters, and metabolite inter-conversions.