In a captivating webinar led by industry experts, Dr. Swati Jaiswal, Senior PBPK Consultant at Certara, and Dr. Erica Winter, Director of Clinical Pharmacology at EQRx, Model-Informed Formulation Development (MIFD) took center stage. The session provided valuable insights into the strategic utilization of model-informed approaches in drug development projects. A compelling case study on development of an extended release (ER) formulation for a drug with low permeability and solubility in vitro shed light on the potential benefits of this innovative approach.
Challenges of Twice-Daily Dosing:
The webinar began by addressing a pressing issue faced by patients with chronic inflammatory disease – the unacceptably high pill burden and adherence challenge associated with twice-daily dosing of the immediate release (IR) formulation. Acknowledging this concern, the drug’s sponsor sought an effective solution that would significantly improve patient experience and compliance.
The Quest for an Optimal Solution:
To address the challenges, the team aimed to develop and validate a physiologically-based pharmacokinetic (PBPK) model using the Simcyp Simulator. This model would serve as the foundation for guiding the developing an ER drug formulation, designed to be taken once daily.
Decisions Based on Short Half-Life:
The short half-life of the drug candidate of only 2 hours presented the clinical pharmacology team with a crucial decision-making juncture. They needed to choose between administering high doses of the drug, leading to an unacceptably high Cmax (maximum concentration), or pursuing the innovative ER formulation with a once-daily regimen.
Safety and Compliance Considerations:
Understanding the potential risks associated with an elevated Cmax, such as off-target safety events linked to the mechanism of action of the drug candidate and known safety concerns within its class, a high Cmax was deemed unacceptable. Thus, the pursuit of a more patient-friendly ER formulation with once-daily dosing became imperative.
Strategic Positioning in the Market:
Beyond patient considerations, the strategic positioning of this drug candidate in the competitive landscape was also crucial. Given the presence of several other compounds on the market offering a once-daily dosing option, adopting this regimen became a necessity to stay relevant and competitive.
Key Takeaways:
Model-Informed Formulation Development Optimizes Development Process:
The webinar provided valuable insights into the immense impact of MIFD on drug development. By leveraging PBPK modeling, the team successfully developed an extended-release formulation within a timespan of several months, using a limited number of healthy participants and without the use of animals, for their drug candidate. Dr. Winter eloquently described how their approach included the development of a PBPK model to guide the prototype development of the extended-release formulation. The versatility of the model extended beyond formulation development, proving to be a valuable tool in assessing drug-drug interaction risks and projecting pediatric doses. Attendees were inspired by the potential of MIFD in optimizing drug performance and streamlining the development process.
Predictive Modeling Reduces Time and Cost:
Dr. Jaiswal emphasized the criticality of confidence in the developed PBPK model, which allowed them to predict the PK behavior of the drug candidate. This predictive approach captured the intricate interplay between dissolution and absorption occurring in vivo. The human PBPK modeling based assessment was more predictive and directive for optimizing ER formulation compared to dog studies. The importance and advantages of using a mechanistic and /or semi-mechanistic approach for predicting in vivo dissolution for IR and ER formulations using aqueous and bio-relevant solubility data were discussed specifically for low solubility compounds. Also, the current knowledge gaps associated with ER (extended-release) / MR (modified-release) formulations dissolution predictions were highlighted. The attendees learned how a data-driven, model-informed strategy could effectively expedite drug development timelines and lower costs, offering promising implications for the pharmaceutical industry.
Establishing a PK Model Early Yields Multiple Benefits:
Establishing a PBPK model in early development provides a strategic advantage. The PBPK model served as a guiding beacon throughout the process, steering the team in the development of extended-release prototypes. Beyond this, the versatility of the model extended to assessing potential drug-drug interaction risks, providing valuable insights that otherwise would have been challenging to obtain. Dr. Winter emphasized the iterative nature of their approach, allowing them to swiftly identify an effective extended-release formulation and stay agile in their decision-making process.
Insights Surfaced:
Throughout the webinar, attendees gained a comprehensive understanding of the significance of integrating model-informed approaches early on in drug development and formulation projects. The case study exemplified how a well-developed and validated PBPK model could catalyze formulating a successful extended-release drug. The interdisciplinary collaboration between PBPK consultants, clinical pharmacologists, and formulation experts played a pivotal role in achieving successful outcomes.
Key Quotes:
“Modeling for formulation development is quite effective… it will significantly reduce the time and cost involved in the formulation development.” – Dr. Erica Winter, Director of Clinical Pharmacology at EQRx.
“Once you have established a PBPK model, it is going to be useful and provide advantages in terms of time and cost, accelerating and rationalizing your formulation development process, making it more science driven.” – Dr. Swati Jaiswal, Senior PBPK Consultant at Certara.
“We were able to evaluate multiple ER prototypes and identify the final extended-release formulation for clinical advancement within several months.” – Dr. Swati Jaiswal, Senior PBPK Consultant at Certara.
Conclusion:
The webinar showcased how Model-Informed Formulation Development can revolutionize the drug development process. The development and validation of a PBPK model proved to be a pivotal step in successfully guiding the formulation of an extended-release drug, resulting in significant time and cost reductions. By capitalizing on model-informed approaches early on, researchers can make informed decisions, optimize drug performance, and expedite formulation development, ultimately driving progress in the field of drug development and benefiting patients worldwide. The webinar’s insights resonated with attendees, leaving them inspired to leverage predictive modeling and interdisciplinary collaboration in their own drug development endeavors. As the pharmaceutical industry continues to embrace model-informed approaches, the future holds tremendous promise for scientific advancements and improved patient outcomes.
For a comprehensive review of the case study presented in our webinar, we invite you to explore this MIFD whitepaper. In addition to the case study, the whitepaper provides a deeper dive into how Model-Informed Drug Development (MIDD) is actively supporting drug development and facilitating regulatory review processes. Don’t miss this valuable resource!