PBPK-informed design of formulation prototype in the context of a sustained release formulation development

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

What is the in vitro dissolution profile of a sustained release prototype formulation of flucytosine (5FC) allowing to meet target PK profiles, with a twice daily administration, in HIV patients with cryptococcal meningitis? 

This work supported the design of the 3 sustained release prototypes for a clinical study aiming at comparing 3 different release rate (slow, intermediate and fast) sustained release formulations of 5FC to the existing immediate release formulation (Medium impact).

Predicted PK profiles at steady-state after administration of sustained release prototypes twice daily in healthy volunteers (upregiment corresponds to Lint80 dissolution profile; bottom/blue corresponds to Weibull dissolution profile). Lines correspond to typical profiles, shaded areas to 80% prediction intervals and dotted lines to the therapeutic interval.

PBPK model developed solely from literature data (no IV data, only per os).

Pharmetheus was responsible for the MIDD strategy and the PBPK modeling and simulation. Pharmetheus proposed 2 different in vitro release rate profiles which should allow to meet PK target profile and lead to sufficiently different in vivo PK profiles (20% difference).

Physiologically-based biopharmaceutics modelling (PBBM), physiological  in vitro in vivo relationship (IVIVR) by convolution.