Food effect prediction and dose selection, using PBPK/PBBM, in the context of a switch from an immediate release to a sustained release formulation

• Therapeutic area: Infectious Diseases
• Development stage: Phase I
• Modeling strategy: PBPK-PBBM, MIDD (Model-Informed Drug Development)
• MIDD Impact category: Inform

Using the previously developed PBPK model and based on assumptions about the food effect mechanism, PBPK predictions supported the design of the food interaction study to come. After the study completion, the model was refined confirming food effect mechanism hypotheses.

What is the food effect on flucytosine (5FC) PK profile after administration of a sustained release formulation in the context of a switch from immediate release to sustained release, for cryptococcal meningitis treatment in HIV patients?

This work supported the dose selection for a food interaction study with the SR formulation and later served to make recommendations toward food intake to patients (Medium impact).

Predicted PK profiles, in fed state (before model refinement) after administration of the immediate (left panel) and sustained release (right panel) formulation (line corresponds to typical profile and shaded area to the 90% range of a virtual population (n=200)). Assumptions: 1) Gastric transit time is increased by food intake. 2) No change in solubility by the food intake (hydrophilic drug).

Predicted PK profiles using the refined model, after multiple dose administration of the optimal fed dose in fasted condition (left panel) and after administration of optimal fasted dose in fed state (right panel) of the sustained release formulation (line corresponds to typical profile and, shaded area to the 90% range of a virtual population (n=200)prediction interval).

• To predict the food effect on 5FC PK after administration of the sustained release formulation based on 5FC physicochemical properties and biological knowledge.
• To refine the legacy model using food interaction clinical data by testing hypotheses about the food interaction mechanism on 5FC release and absorption.

Pharmetheus was responsible for the MIDD and the PBPK modelling and simulation, and participated in project team discussions about food interaction study design and food intake recommendation.

Physiologically-based pharmacokinetics modeling (PBPK) of food effect implemented in PK-Sim® software.