Model-informed drug development of flucytosine sustained release formulation in the treatment of cryptococcal meningitis: A case study using PBPK modeling

This publication is about the application of Model-Informed Drug Development (MIDD) and early integration of modeling in developing a sustained-release (SR) formulation of flucytosine for cryptococcal meningoencephalitis (CM) in HIV-infected patients.
It showcases how Physiologically Based Pharmacokinetic (PBPK) and Physiologically Based Biopharmaceutics Modeling (PBBM) guide key decisions throughout the drug development process, ensuring optimal therapeutic strategies.

Key highlights of the study:

• MIDD strategy: Leveraged PBPK/PBBM modeling to support decision-making throughout the drug development, i.e., from formulation prototype design to phase 2 design with the selected formulation. 
• Adapting to challenges: Simulations for evaluating loading dose strategies and drug exposure in unconscious patients enabled rapid, data-driven decision-making.
• Optimized dosing: Modeling played a critical role in determining the right dosing for an upcoming Phase 2 clinical study, focusing on patient populations with low body weight and risk assessment for gastro-intestinal disease-related attributes.

This work emphasizes the power of MIDD in accelerating drug development and optimizing treatment outcomes by providing adaptable, reliable models that can respond to evolving challenges. With continuous knowledge integration, we demonstrate how PBPK/PBBM modeling can not only drive formulation and dosing decisions but also enhance therapeutic development, ultimately benefiting patients in need.