Commercial and health impacts of drug modelling tools
Submitting InstitutionUniversity of Sheffield
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Neurosciences, Pharmacology and Pharmaceutical Sciences
Summary of the impact
Research at the University of Sheffield developed pharmacokinetic tools
that enable prediction of drug absorption, distribution, metabolism and
excretion, and potential drug-drug interactions. In 2001 the University
created a spinout company, Simcyp Ltd, to commercialise the technology.
The impacts are:
- Commercial: the company was awarded the Queen's Award for Enterprise
in Innovation in 2010 and in February 2012 was sold for $32M to Certara,
a leading provider of drug discovery and development software.
- Commercial: the Simcyp population-based Simulator is now used in drug
development by many of the world's leading pharmaceutical companies,
saving them time and millions of dollars through more efficient and
- Health: human and animal test subjects have benefitted by optimisation
of the design of trials to minimise unnecessary drug exposure.
- Health: the Simcyp Paediatric module has improved the care of children
by providing reliable evidence to better guide dosage.
The handling of a drug by the body can be very complex, as several
processes (such as absorption, distribution, metabolism, and elimination)
work to alter drug concentrations in tissues and fluids. The perceived
failure of new drug development has been blamed in part on deficiencies in
understanding how human populations handle such drugs.
Prior simulation of the potential exposure of different individuals to a
given dose of drug and how they metabolise and react to this drug might
help to improve the design of clinical trials. Simplifications of body
processes are necessary to predict a drug's behaviour in the body. One way
to make these simplifications is to apply mathematical models and computer
simulations to the various processes.
Professors Tucker (UoS 1972-2009) and Rostami-Hodjegan (UoS 1996-2009)
were interested in clinical trial simulation and developed computer
programmes to assess how drugs were metabolised in human populations.
Using programmes that were developed using FORTRAN they attempted to
simulate pharmacokinetic (what the body does to the drug) behaviour in
`virtual populations' taking into account demographic, physiological and in
vitro biochemical data (R1, R2).
In 1999, they started to incorporate their algorithms into Windows-based
software as part of the Simcyp Simulator Project. The project was a
cooperative venture with a consortium of pharmaceutical companies. It had
the objective of developing a user-friendly programme and database with
simple visual outputs that could be used to predict in vivo
pharmacokinetics in virtual adult patient populations (R3). This was also
extended to pharmacokinetics in children (R4).
The Simcyp Simulator (R5) has evolved to include extensive demographic,
physiologic and genomic databases that have allowed the development of
algorithms which account for patient variability. This enables drug
companies to predict drug behaviour in the virtual patient population, as
opposed to a virtual reference man, allowing individuals at extreme risk
to be identified. This has facilitated decision making in the early
clinical stages of drug development and also minimises unnecessary drug
testing on humans and animals. The Simulator continues to evolve and is
now used in the investigation of pharmacodynamics (what the drug does to
the body, R6).
References to the research
R1. Rostami-Hodjegan A, Nurminen S, Jackson PR & Tucker GT. Caffeine
urinary metabolite ratios as markers of enzyme activity: a theoretical
assessment. Pharmacogenetics. 1996; 6: 121-49. doi: 10.1097/00008571-199604000-00001
R2. Rostami-Hodjegan A, Peacey SR, George E, Heller SRR & Tucker GT.
Population-based modeling to demonstrate extrapancreatic effects of
tolbutamide. Am J Physiol. 1998; 274: E758-E771. PubMed ID: 9575839
R3. Moghadamnia AA, Rostami-Hodjegan A, Abdul-Manap R, Wright CE, Morice
AH, Tucker GT. Physiologically based modelling of inhibition of metabolism
and assessment of the relative potency of drug and metabolite:
dextromethorphan vs. dextrorphan using quinidine inhibition. Br J Clin
Pharmacol. 2003; 56: 57-67. doi: 10.1046/j.1365-2125.2003.01853.x
R4. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the
clearance of eleven drugs and associated variability in neonates, infants
and children. Clinical Pharmacokinetics. 2006; 45: 931-56. doi: 10.2165/00003088-200645090-00005
R5. Jamei M, Marciniak S, Feng K, Barnett A, Tucker G &
Rostami-Hodjegan. The Simcyp population-based ADME simulator. Expert Opin
Drug Metab Toxicol. 2009;5 :211-223. doi: 10.1517/17425250802691074
R6. Dickinson GL, Lennard MS, Tucker GT, Rostami-Hodjegan A. The use of
mechanistic DM-PK-PD modelling to assess the power of pharmacogenetic
studies -CYP2C9 and warfarin as an example. British Journal of Clinical
Pharmacology. 2007; 64: 14-26. doi: 10.1111/j.1365-2125.2007.02850.x
Details of the impact
The Sheffield research, via the spin-out company Simcyp, has delivered
commercial and health impact worldwide, thanks largely to its innovative
and firmly user-driven business model. Since its inception, all customers
have directly steered product development through the Simcyp Consortium,
voting on priorities for annual upgrades to ensure the product remains
current and closely matched to end-user needs. Consortium members also
provide routine data from their own trials, keeping the simulator as
accurate as possible through the addition of large volumes of real test
data. The accuracy and reliability encouraged several national regulatory
bodies to accept Simcyp's modelling as evidence in licensing new drugs.
This combination of user-focus, accuracy and regulatory recognition,
coupled with the significant commercial benefits described below, has
attracted more than 20 of the world's top 25 pharmaceutical companies to
buy licences, including AstraZeneca, Eli Lilly, Johnson & Johnson,
Merck, Novartis and Pfizer.
Simpcyp was spun out from the University of Sheffield in 2001 (S1).
Turnover in 2006 was £1M increasing every year to £4.7M in 2010. This was
associated with a £0.2M post-tax profit in 2006 rising to £1.9M in 2011
(S2). It was 15th fastest growing UK company in 2009 (S3) and
as at 31 July 2011 the number of employees was 47 (S2). In 2012 Simcyp was
sold to Certara for $32M (S4, S5).
The company also delivers significant benefits for its industrial
customers. It can take 12 years and £1 billion to bring a new drug to
market. Simcyp allows manufacturers to eliminate dangerous or unsuitable
compounds at an early stage and focus solely on potentially viable drugs.
By cutting short the early testing phase, they can save time and many
millions of dollars that they would otherwise spend testing drugs that
would later fail in clinical trials.
Simcyp won the Queen's Award for Enterprise in Innovation in 2010 (S6).
Health and Wellbeing
The extensive use of Simcyp by the industrial pharma community has
delivered two distinct impacts on health and wellbeing.
Firstly, by optimising the design of trials it has minimised unnecessary
drug exposure among human volunteers and animal test subjects. Its
contribution to humane research was recognised in 2009 with an OSCAR
(Outstanding Scientific Contribution to Animal Replacement, from the UK's
leading non-animal medical research charity, The Dr Hadwen Trust for
Humane Research [S7].
Secondly, the Simcyp Paediatric Simulator provides valuable information
relevant to first-time dosing decisions and the design of clinical studies
in infants, neonates and children. It also helps pharma companies meet
their obligations under EU regulations. A Senior Pharmacist at Sheffield
Children's Hospital and Senior Scientist at Simcyp outlines the tool's
"Traditional dosing decisions have often been taken under the false
assumption that young children are simply little aduts. This model takes
into account the many changes in pharmacokinetics which occur as a
result of organ maturation and changes in body composition and drug
elimination pathways. Fewer than 50% of children's medicines have
actually been tested in an appropriate age group. Simpcyp Simulations
allow a clinical study in children to become `confirmatory' rather than
`exploratory', reducing unnecessary drug exposure. This is crucial now
that EU regulations insist that paediatric data be included in all
applications for new medicinal products."
Sources to corroborate the impact
S1. Simcyp website gives details of company's history: http://www.simcyp.com/
S2. Simcyp turnover, post-tax profit and employee number figures
2006-2010 from Operations Director, Fusion IP available on file.
S3. Reference to 15th fastest growing UK company in 2009. The
Business XL Top 50 Rising Stars is an annual ranking of UK-based fast
growing companies reporting turnover of between £2.5 million and £100
million and profits of at least £300,000 (http://tinyurl.com/pwhomqz).
S4. Certara media release announcing acquisition of Simcyp (http://tinyurl.com/phthryg).
S5. Acquisition for $32m confirmed in press (http://tinyurl.com/n3xbcor).
S6. Media release from Fusion IP announcing award of Queen's Award for
Enterprise in Innovation to Simcyp: (http://www.fusionip.co.uk/simcyp-wins-queens-award/).
S7. Media release from Simcyp confirming the award of the OSCAR (http://tinyurl.com/modur97).