(W-029) Physiologically based pharmacokinetic modelling to support the development of a sustained-release formulation for the treatment of cryptococcal meningoencephalitis: An MIDD case study

Erik Sjögren, PhD, Associate Professor – PBPK-QSP Platform Scientific Lead, Pharmetheus; Jean-Yves Gillon, PhD – Head of Translation Sciences, Drugs for Neglected Diseases initiative; Vishal Goyal, PhD – Senior Clinical Manager, Drugs for Neglected Diseases initiative; Vijay Satam, PhD – Senior Pharmaceutical Development Manager, Drugs for Neglected Diseases initiative; Stephen Robinson, PhD – Pharmaceutical Development Director, Drugs for Neglected Diseases initiative; Justine Jelagat Odionyi, PhD – Head of Disease, HIV, Drugs for Neglected Diseases initiative; Henri Caplain, MD – Senior advisor in Early Clinical Development, Translational Pharmacology and Safety Risk Management, Drugs for Neglected Diseases initiative; Isabela Ribeiro, MD – Viral Diseases Cluster Director, Drugs for Neglected Diseases initiative; Marylore Chenel, PhD – Chief Research Officer, Pharmetheus

Objectives: Flucytosine (5FC) is a key medication for treating cryptococcal meningoencephalitis (CM), a condition frequently affecting people living with HIV. The current 5FC dosing regimen is an immediate release (IR) tablet formulation that requires administration four times daily, posing challenges for compliance and for patients who cannot tolerate oral medicines [1,2]. To tackle these issues, a sustained-release (SR) pellet formulation of 5FC is currently in development. The development program used a model-informed drug development (MIDD) strategy [3] to guide internal decision-making and facilitate external communications with regulatory authorities.
The aim of this study was to showcase the value of applying an MIDD strategy, in this case by using physiologically-based pharmacokinetic (PBPK) modelling, to guide decisions and optimize therapeutic strategies throughout the drug development process.

Methods: Data from the literature was used to develop a PBPK model for 5FC, which was then refined by including additional data from two Phase I clinical studies in different prandial states, both evaluating the IR and SR formulations. The model included elimination through glomerular filtration, low fraction bound to plasma proteins (3%), high intestinal permeability and solubility, and different IR and SR dissolution according to Weibull functions [4]. A 20-100 mg/L therapeutic range for flucytosine plasma concentrations was used in all assessments.

Results: The PBPK model was used to support several study designs and risk assessments during the development program: first, the design and dosage (3000 mg bid) of the three SR prototypes (formulations B, C, and D) with different release characteristics were suggested for the first Phase I study; second, after refining the model based on the study data obtained, the prototype (formulation D), dose (6000 mg bid) and predicted food effect were suggested for the second Phase-I study; and third, a dosage (6000 mg bid) for the Phase 2 study, which accounted for the impact on the disease was suggested. Several ancillary questions were also assessed, e.g., the need for a loading dose for the SR formulation.

Conclusions: In conclusion, this case study underscores the benefit of using an MIDD strategy and the early integration of models in the drug development process. Utilizing PBPK modeling enabled well-informed decision-making, resulting in the design and dosing of 5FC sustained- release formulation for treating cryptococcal meningitis.

Citations: [1] Vermes A, et al. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. The Journal of antimicrobial chemotherapy 2000; 46(2): 171-9.
[2] Archibald LK, et al. Antifungal susceptibilities of Cryptococcus neoformans. Emerging infectious diseases 2004; 10(1): 143-5.
[3] EFPIA MID3 Workgroup, et al. Good practices in model‐informed drug discovery and development: practice, application, and documentation. CPT: pharmacometrics & systems pharmacology. 2016 Mar;5(3):93-122.
[4] Eriksson J, et al. Physiologically based pharmacokinetic (PBPK) modeling of the oral absorption of 5-flucytosine to support further development of a sustained-release formulation for the treatment of cryptococcal meningoencephalitis. PAGE abstract 2023.