Disease effect prediction on PK 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

How much can the disease impact flucytosine (5FC) PK profile after administration of a SR (Sustained release) formulation in the context of a switch from Immediate Release (IR) to Sustained Release (SR), for cryptococcal meningitis treatment in HIV patients?

This work supported the clinical phase 2 protocol and the discussion with investigators (Medium impact).

Figure of the effect of disease components on 5FC PK profiles after administration of the IR and SR formulations. The black and dotted lines correspond to the medians of simulated profiles after administration of the SR and IR formulations, respectively. The coloured shaded areas correspond to the 90% prediction intervals of the SR formulation.

Table of the effect of disease components on the relative exposure of the SR and IR formulations. Values are expressed as geometric mean ratios (SR/IR).

• To predict the disease effects (i.e., leaky intestine, damaged microvilli, diarrhea due to fast intestinal transit or high-water content, and malnutrition) on 5FC PK after administration of the SR formulation based on 5FC physicochemical properties and physio-pathological knowledge.
• To generate hypotheses about disease effect on release and absorption of 5FC.

Pharmetheus was responsible for the MIDD and the PBPK modeling and simulation, and participated in project team discussion about phase 2 protocol.

Physiologically-based pharmacokinetics.