Certara, the global leader in model-informed drug development, regulatory science, real-world evidence and market access services, today announced the launch of version 18 of its Simcyp Population-based Simulator.
‘I am delighted to introduce Simcyp Simulator v18, which includes several major modelling and simulation advances to help improve the safety and efficacy of new drugs – both small molecules and biologics – under development,’ said Certara’s Simcyp president and managing director Steve Toon, PhD.
‘When we began developing the Simcyp Simulator 20 years ago, we could not have foreseen the major impact the Simulator would have upon the entire drug development process and how it would serve as the catalyst for 35 leading global pharmaceutical companies coming together in a pre-competitive environment to move the mechanistic modelling and simulation field forward through the sharing of open-science. I am very proud of the Simcyp Consortium and that movement, which has helped spur the widespread adoption of model-informed drug development by pharma, academic institutions and global regulators. The Simcyp Simulator has now been used to inform drug label claims, removing the need for specific clinical investigation, for more than 50 new drugs approved by US FDA. As our technology advances, so will its impact upon regulatory decision making,’ added Dr Toon.
Certara’s Simcyp Simulator is the most sophisticated platform for determining first-in-human dose selection, designing more efficient and effective clinical studies, evaluating and advancing new drug formulations, predicting drug-drug interactions (DDIs) and PK outcomes in numerous virtual clinical populations. These include vulnerable populations, such as pediatric patients, pregnant women, and patients with impaired organ function.
Simcyp Simulator v18 advances include the following:
New Tumour Models
It is believed that some of the most intractable oncology drug development challenges, such as improving survival rates for ovarian and pancreatic cancer sufferers, are due to the fact that the drug is not successfully reaching the target site in the tumour. Anticancer drugs’ capacity to treat solid tumours depends upon their plasma PK and their ability to reach their pharmacological target in the malignant tumour.
Version 18 of the Simcyp Simulator helps to quantify how much drug is getting to the target site within the tumour. The Simulator’s permeability limited tumour models now combine knowledge of the tumour composition with the drug’s physicochemical properties to simulate the distribution of small molecule drugs or biologics.
These drug distribution models can also be combined with other tumour growth models, allowing a drug’s concentration in the tumour and the resulting tumour growth or inhibition to be factored in. The Simcyp Simulator can model the impact of a single drug or a combination therapy on the tumour. It can also simulate target-mediated drug disposition in tumour for biologics.
The Simcyp Simulator contains 19 virtual populations for simulating drug performance via bridging, including a cancer patient population that has been leveraged for numerous drug programs.
Enhanced ADAM Model to Predict Back-conversion of Metabolites in the Gut Lumen
In some cases, the drug metabolite can be converted back to the parent drug in the gut lumen. Therefore, it is important to consider the kinetics of both parent drugs and their metabolites – which could be DDI victims or perpetrators – when evaluating safety risk during drug development. The Simcyp Simulator’s Advanced Dissolution, Absorption and Metabolism (ADAM) model, which simulates drug disposition in the gut, has been enhanced to simulate back-conversion of metabolites in the gut lumen.
Many important medications are pro-drugs, i.e. the primary ‘metabolite’ of a pro-drug is the pharmacologically active moiety rather than the parent compound (pro-drug). DDIs mediated by drug metabolites formed by gut bacteria can and have caused serious adverse events, including death. For example, sorivudine had to be withdrawn from the market within 40 days of approval due to lethal gut lumen (microbiota)-driven metabolic DDI with tegafur.1
Updates to ADAM permit simultaneous modelling of the inter-conversion of parent compound to metabolite, entero-hepatic re-circulation, and efflux to the gut lumen, as well as metabolism- and/or transporter-mediated DDIs in the gut.
Expansion of Trial Design to Allow Food and Fluid Staggering
Drug-food effects can pose a serious safety issue and are an important element on the drug label. Therefore, regulators expect sponsors to have a good understanding of a new compound’s drug-food effects. If drug-food effects are determined not to be an issue, it removes a burden from patients and it is one less factor that sponsors have to control in their clinical studies.
To help investigate and determine the optimal time for patients to consume food and fluids with their medication, the Simcyp Simulator now offers a “food-staggering” simulation capability. This allows clinical trials to be designed with independent drug dosing, meal, and fluid intake times in addition to the existing “fed” and “fasted” options. Several new Simcyp Simulator models ensure the relevant physiological parameters are adjusted as patients transition between fasted-fed and fed-fasted states. These additions include a new dynamic bile salts model, an improved fluid volumes dynamics model, and time-dependent intestinal and stomach pH models. As the fat content of a meal can also impact drug disposition, the Simcyp Simulator now also includes the FDA’s “High fat diet based gastric pH model.” These advances enable sponsors to model more real-life scenarios.
Mechanistic Absorption Models
Certara, in partnership with the University of Leuven in Belgium, is working under an FDA Office of Generic Drugs grant to develop and qualify the PBPK modelling and simulation framework that enables the Simcyp Simulator to simulate and predict the behaviour of supersaturating orally-dosed drug products in the human gastrointestinal tract. As part of this development, the ADAM oral absorption model has been expanded significantly with the addition of a particle population balance (PPB) model. The new model enables simulating two different solid states of a drug to be handled simultaneously, including precipitation to a solid-state different to that of the dosage form, precipitation to two solid states simultaneously, and modelling of formulations where there has been partial solid-state conversion during storage. A nucleation model has also been incorporated, which is run as a competing process with particle growth, including growth of never-dissolved particles from the dosage form.
New Reverse Translation Tool (RTT)
Many of the input parameters for the Simcyp Simulator are derived from in-vitro experiments. However, sometimes the requisite in-vitro data are not available, but clinical data are. The Simcyp Simulator now has a sophisticated mechanistic ‘Reverse Translation Tool’ built to complement the retrograde model allowing researchers to take an in vivo value, such as an observed clearance, and work backwards to determine the original in-vitro values. Further, an iterative approach is developed to calculate UGT-mediated intrinsic clearances in both liver and kidneys. The new tool offers more flexibility in study populations and selection between Extensive Metabolizers (EM) and other population phenotypes. The retrograde model, which was originally developed to create pediatric PBPK models, has been used to extrapolate data to other patient populations.
Expanded Compound Library
Certara has continued to expand its compound database; it is committed to providing compound qualification summaries for every new compound released as well as providing updated summaries for the existing compounds. These documents provide background on compound parameters and demonstrate the Simcyp Simulator’s ability to mimic clinical studies. They are used by sponsors to support regulatory interactions with health authorities.
Further information about the new Simcyp Simulator v18 attributes is available via a one-hour archived webinar at https://www.certara.com/webinar-archive/whats-new-in-the-simcyp-simulator-v18/?ap%5B0%5D=PBPK&UTM_LeadSource=12052018.
Reference
1. Okuda et al. A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. J Pharmacol Exp Ther. https://www.ncbi.nlm.nih.gov/pubmed/9808711
