Clémence Rigaux, Marion Bouillon-Pichault, Bernard Sébastien, Kimiko Koiwai, Cathy Cantalloube
Sanofi R&D, Paris, France
Objectives: Ferroquine (FQ) is an anti-malarial drug currently being developed in combination with OZ439. Population pharmacokinetic models of FQ and its active metabolite SSR97213 after oral administration have been developed internally using blood concentration-time data from a pool of phase I and II studies that include healthy adult subjects, as well as adult and paediatric patients. The objective of this analysis is to develop and qualify a population pharmacokinetic-pharmacodynamic (PKPD) model for FQ and its active metabolite SSR97213 to describe parasitemia clearance using data from a Phase II study (DRI10382) in P. falciparum infected patients.
Methods: Data from the FQ-alone arm of a Phase IIb study were used to develop a non-linear mixed effect model using Monolix 4.3.3. PK and parasitemia data came from 79 symptomatic adult and paediatric (4-74 years) patients receiving 4 mg/Kg/day of FQ over 3 days. FQ and SSR97213 PK were described by the already available PK model. Parasite counts after rescue therapy or re-infection were discarded from the development database.
Results: Parasitemia was described by a simple first-order model. Periodic oscillations were applied to both first-order growth and degradation phase and a FQ effect on degradation phase was applied using an Emax function. A parasitemia threshold was used as an estimate of parasitemia below which recrudescence will not occur. In order to get unbiased diagnostic plots, a time-to-event model for rescue-therapy intake was also developed, where rescue-therapy intake depends on parasitemia levels and time. Diagnostics plots like VPC show that the model correctly predicts parasitemia for early times.
Conclusions: This model is a first step for developing a PKPD parasitemia model for the FQ-OZ439 combination. This FQ model, combined with an OZ439 model and data coming from the FQ/OZ439 combination, could be used to simulate clinical efficacy endpoints for different dosing regimens of FQ-OZ439 combinations in adults and children.
Reference: PAGE 25 (2016) Abstr 5881 [www.page-meeting.org/?abstract=5881]
Poster: Drug/Disease modeling - Infection