Simcyp Simulator - a comprehensive platform and database for mechanistic modelling and simulation of oral drug absorption, tissue distribution, metabolism and elimination in healthy and disease populations using in vitro knowledge
Jamei M, Howgate E, Aarabi M, Ghobadi C
Simcyp is a University of Sheffield spin-out company that develops algorithms along with population and drug databases for modelling and simulation (M&S) of the absorption and disposition of drugs in patients and specific subgroups of patients across different age ranges. The Simcyp models use experimental data generated routinely during pre-clinical drug discovery and development from in vitro enzyme and cellular systems as well as any relevant physico-chemical attributes of the drug and dosage forms.
The Simcyp Population-based ADME Simulator is licensed to Simcyp's Consortium member clients for use in drug discovery and development. The Consortium guides scientific development at Simcyp, ensuring that the platform and databases continue to meet, and in many cases exceed, industry needs. Simcyp maintains strong academic links and our science team conducts internationally recognised cutting-edge research and development which accelerates decision making in drug discovery and development for member pharmaceutical companies. The Simcyp science team:
- provides a user friendly simulator that integrates genetic information on drug metabolising enzymes into PBPK models for the prediction of drug disposition in diverse patient populations with relevant demographic and physiological characteristics,
- offers consultancy and advice on a broad spectrum of DMPK issues (including optimal study design for metabolic drug-drug interactions, data interpretation, prediction of in vivo ADME from in vitro studies, dose selection for different age groups particularly in neonates and young children, assessing the likely effects of renal impairment, cirrhosis and ethnic variations on ADME, etc)
- delivers an educational program consisting of hands-on workshops and courses covering concepts and applications of in vitro - in vivo extrapolation (IVIVE) to predict drug clearance, drug-drug interactions, gut absorption handling metabolism/transport interplay, and covariates that determine drug disposition (see http://www.simcyp.com/ProductServices/Workshops/)
Currently, 9 of the top 10 pharmaceutical companies worldwide have access to Simcyp expertise through Consortium membership. Members include AstraZeneca, Biovitrum, Daiichi-Sankyo, Eli Lilly, F.Hoffman-La Roche, Lundbeck, Novartis Pharma, Nycomed, Otsuka, Pfizer, sanofi-aventis, Servier, Takeda and UCB Pharma among others. The aim of the Consortium is to help members enhance the utilisation of information from pre-clinical development in the rational selection and design of in vivo studies. Value is added to decision-making processes by collaboration with regulatory bodies (the FDA, MPA, NAM, ECVAM) and academic centres of excellence worldwide, also within the framework of the Consortium.
In the demonstration session we provide an overview of the capabilities of the Simcyp Simulator to predict drug absorption, clearance and metabolic drug-drug interactions and PBPK modelling from in vitro and physiochemical information in diverse populations including paediatric, obese, cirrhosis and renally impaired. Some details of the scientific background to Simcyp's approaches can be found in our recent publications:
- Yang JS et al. Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Clinical Drug Interactions. Current Drug Metabolism, (in press).
-Rostami-Hodjegan A and Tucker GT. Simulation and prediction of in vivo metabolic drug clearance from in vitro data. Nature Reviews 6(2), 140-149, 2007.
- Yang JS et al. Prediction of intestinal first-pass drug metabolism. Current Drug Metabolism 8(7), 676-684, 2007.
- Yang JS et al. Theoretical assessment of a new experimental protocol for determining kinetic values describing mechanism (time)-based enzyme inhibition, Eur J Pharma Sci, 31(3-4), 232-241, 2007.
Perrett HP et al. Disparity in holoprotein/apoprotein ratios of different standards used for immunoquantification of hepatic cytochrome P450 enzymes. Drug Metabolism & Disposition 35(10), 1733-1736, 2007.
Yang JS et al. Misuse of the Well-Stirred Model of Hepatic Drug Clearance, Drug Metabolism and Disposition, 35(3), 501-502, 2007.
Van LM et al. Inactivation of CYP2D6 by methylenedioxymethamphetamine in different recombinant expression systems. Eur J Pharma Sci, 32(1), 8-16, 2007.