What’s New in the Simcyp Simulator v18?

Sponsors and regulatory agencies routinely use physiologically-based pharmacokinetic (PBPK) modeling and simulation to assist in dose selection and inform product labeling. Certara’s PBPK platform, the Simcyp® Simulator, links in vitro data to in vivo ADME (absorption, distribution, metabolism, and excretion) and pharmacokinetic/pharmacodynamic (PK/PD) outcomes to help explore potential clinical complexities prior to human studies and support decision-making in drug development.

Watch this webinar with Nikunjkumar Patel, Shriram Pathak, and Rachel Rose to learn how the latest updates in the Simcyp Simulator v18 will help support developing safer, more effective medications. These enhancements include:

  • Ability to Model Entero-hepatic Recirculation for Metabolites and Gut Luminal Disposition: Many important medications are pro-drugs where the parent compound is metabolized to the primary metabolite (M1) which exerts the therapeutic effect. In some cases, M1 can be converted back to parent within the gut lumen, for example, glucuronide metabolites. Drug-drug interactions (DDIs) even at gut luminal level are a critical safety consideration during drug development. For example, sorivudine had to be withdrawn from the market within 40 days of approval due to lethal gut lumen (microbiota)-driven metabolic DDI with tegafur (Okuda et al. 1998 JPET). Parent drugs and metabolites can be DDI victims or perpetrators. Thus, understanding the kinetics of drugs and their metabolites within the gut is important to predicting potential DDIs. The Simcyp Simulator’s Advanced Dissolution Absorption and Metabolism (ADAM) model is used to model drug disposition in the gut. Recent updates to the ADAM model allow the following processes to be modeled simultaneously: inter-conversion of parent to M1, entero-hepatic re-circulation of parent as well as M1, efflux of parent and M1 to the gut lumen, and metabolism- and/or transporter-mediated drug-drug interactions in the gut. These updates allow increased flexibility to simulate potential complex parent and metabolite inter-conversion clinical scenarios.
  • Development of Tumor Models to Describe Small and Large Molecule Drug Distribution: The efficacy of anticancer drugs for the treatment of solid tumors depends not only on their plasma pharmacokinetics but also their ability to distribute to their pharmacological target within malignant tumors. Permeability limited tumor models enable modeling of drug distribution for small molecules and large molecules (“biologics”) using knowledge of the tumor composition and drug properties. Target-mediated drug disposition can also be modeled for biologics. The tumor distribution models for both small molecules and large molecules can be integrated with tumor growth models, enabling drug concentration in the tumor to drive tumor growth inhibition and accounting for the effect of tumor growth or growth inhibition on drug distribution. Tumor growth inhibition can be modeled by either built-in models or custom models. The latter can simulate more complex scenarios such as drug induction of efflux transporters or metabolic clearance. The tumor growth inhibitory effect of either single drug or combination therapy can be simulated too.
  • Expansion of Trial Design to Allow Food and Fluid Staggering: Knowing what and when patients can consume food and fluids with their medication is critical for maximizing a drug’s risk-benefit profile and optimizing clinical trial designs. To expand absorption modeling capabilities and to help users simulate a variety of food and fluid intake scenarios, we updated the custom trial design features within the Simulator. In addition to the existing “Fast” and “Fed” simulation options, the new “Food Staggering” framework permits simulating trial designs with independent drug dosing, meal, and fluid intake times. In support of this, the Simulator can now handle fasted-fed (fed-fasted) transitions of relevant physiological parameters including a major new dynamic bile salts model, an improved fluid volumes dynamics model, and a time-dependent intestinal and stomach pH models. A user-friendly graphical tool enables visualizing the virtual trial schedule including multiple feeding, fluid volume, and substrate/inhibitor dose administration times. The overall dose/food/fluid intake scheme can be exported for inclusion in reports. The fat content of a meal can impact drug disposition. Thus, the Simulator has also been equipped with the FDA “High Fat diet based gastric pH model.”