Certara, a provider of decision support technology and consulting services for optimizing drug development and improving health outcomes, has announced that the Office of Generic Drugs (OGD), FDA has awarded it a multi-year research grant to create and validate a physiologically-based pharmacokinetic (PBPK) modeling and simulation framework that complements existing models within the Simcyp Population-based Simulator. The new models will predict and simulate the behavior of supersaturating orally-dosed drug products in the human gastro-intestinal (GI) tract. This platform will also permit new product performance to be assessed and compared to reference products.

“We are proud to be working with the FDA and the University of Leuven in Belgium on this important project. Together, we are leveraging the advances in regulatory science and computing power to find new ways to recognize the value provided by model-based drug development,” said Certara CEO Edmundo Muniz, M.D., Ph.D. “This new modeling framework will eventually be used to perform virtual bioequivalence studies and virtual assessments of food effects on the in vivo behavior of low solubility drugs, thus avoiding unnecessary clinical studies when the outcomes can be predicted accurately using the models.”

The Simcyp Simulator, which includes a sophisticated and well recognized oral absorption module—the Advanced Dissolution Absorption and Metabolism (ADAM) model—already includes fluid dynamics models and physiological fluids. It can simulate clinical trials and predict variability between individuals in different populations rather than just for an “average person.” The Simulator is complemented by the separate Simcyp In Vitro Data Analysis (SIVA) Toolkit considered essential for model validation and extracting appropriate parameters from in vitro experiments prior to performing in vivo simulations.

A very high proportion of new drug candidates are poorly soluble which can severely limit their bioavailability. In order to ameliorate this issue a widely used approach is to formulate to create supersaturated solutions of drug. However, supersaturated solutions carry with them a precipitation risk which can severely limit the intended benefits of this approach. Thus, the ability to anticipate these properties and react accordingly can be critical to the success of a drug development program. This new project aims to further develop state-of-the art mechanistic models and workflows to improve the prediction of the in vivo behavior of supersaturating drug products. The models should enable sponsors to employ appropriate formulation strategies and either prevent precipitation or mitigate its impact earlier than before.

Dr. David Turner, principal scientist at Simcyp and the principal investigator on the grant said, “Prediction of supersaturation and precipitation kinetics of drugs and drug products especially in the complex, variable GI luminal environment is a challenging task. However, with the advance of biomimetic in vitro experiments coupled to state-of-the art mathematical models of nucleation and crystal growth, the team will develop robust approaches to predict the oral absorption profiles of drugs from such products.”

“Simcyp will develop physiologically-based mechanistic supersaturation and precipitation models along with a supporting physiology and variability database,” said Professor Augustijns from the Drug Delivery and Disposition Unit in the Department of Pharmaceutical and Pharmacological Sciences at the University of Leuven. “My team performs in vitro and clinical studies with supersaturating formulations which are to be used to validate Simcyp’s models. We will validate the platform and database against clinical pharmacokinetic data on the available drug products.”