Simcyp Simulator - a comprehensive platform and database for mechanistic modelling and simulation of drug absorption, tissue distribution, metabolism, transport and elimination in healthy and disease populations using in vitro knowledge
Jamei M, Feng F
Simcyp Ltd
Simcyp Simulator–
a comprehensive platform and database for mechanistic modelling and simulation of
drug absorption, tissue distribution, metabolism, transport and elimination in healthy
and disease populations using in vitro
knowledge
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
particularly powerful tool in carrying out virtual clinical trials for recognition
of covariates of PK and optimising early in man studies. The platform and its database
are 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,
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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)
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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, 13 of the top 15 pharmaceutical companies
worldwide have access to Simcyp expertise through Consortium membership. Members
include Actelion, AstraZeneca, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson
PRD, Lundbeck, Novartis Pharma, Nycomed, Otsuka, Pfizer, sanofi-aventis, Servier,
Takeda, UCB Pharma and Wyeth 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 from gut,
lung and skin, enterohepatic recirculation, clearance and metabolic drug-drug interactions,
transport in the gut and liver and PBPK modelling from in vitro and physiochemical
information in diverse populations including paediatric, obese, cirrhotic and renally
impaired.
Some details of the scientific background to
Simcyp’s approaches can be found in our recent publications:
- Johnson TN et al.
Assessing the efficiency of mixed effects modelling in quantifying metabolism based
drug-drug interactions: using in vitro data as an aid to assess study power
Pharm Stat. [Epub ahead of print].
- Jamei M
et al.
Population-based mechanistic prediction of oral drug absorption, The AAPS Journal,
[Epub ahead of print].
- Jamei M
et al.
A framework
for assessing inter-individual variability in pharmacokinetics using virtual human
populations and integrating general knowledge of physical chemistry, biology, anatomy,
physiology and genetics: a tale of ‘Bottom-Up’ vs ‘Top-Down’ recognition of covariates,
Drug Metabolism & Pharmacokinetics, 24(1), 53-75, 2009.
- Jamei M
et al.
The Simcyp® Population-Based ADME Simulator, Expert Opinion On Drug Metabolism
and Toxicology, 5(2), 211-223, 2009.
- Yang J
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, 9(5), 384-394, 2008.
-
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.