Dose Regimen Assessement For Oral Fexinidazole
V. Gualano (1), M. Felices(2), E. Evene(2), S. Blesson(3), A. Tarral(3
(1) PhinC Development, Evry, France, (2) SGS Aster, Paris , France, (3) Drugs for Neglected disease initiative (DNDi), Geneva, Switzerland
Objectives: Fexinidazole, a 5-nitroimidazole, is being developed as a new oral treatment for Human African Trypanosomiasis. The aim of the present study was to determine the efficient dosing schedule for a phase II/III study based on a population pharmacokinetic (PK) model.
Methods: The population PK analysis was performed using NONMEM VI and SAS 9.2 based on plasma samples from data collected through three phase 1 studies, validated using the data of a fourth study (Multiple Ascending Dose over 10 days under fed condition using two different loading dose regimen).
Results: The PK of fexinidazole was best described by a two compartment model with a zero order absorption process. Integration of M1 and M2 metabolites in the model was successful and allowed simultaneous fitting of the three compounds. Population PK parameters of the parent drug estimated in the complete model were in agreement with those reported by non-compartmental analysis. The model simulates the time course of concentration of fexinidazole, M1 and M2 in a typical subject, following multiple once daily oral administration of fexinidazole under fasting and fed conditions. The following dosing regimens under fed conditions were determined from the simulations and implemented in the fourth phase I study:
-1800 mg fexinidazole or placebo from Day 1 to Day 4, and 1200 mg fexinidazole or placebo from Day 5 to 10
-2400 mg fexinidazole or placebo from Day 1 to Day 4, and 1200 mg fexinidazole or placebo from Day 5 to 10. This treatment regimen was found to be poorly tolerated and was stopped
Observed data of the first dosing regimen were in agreement with simulated data obtained with the first treatment schedule. Safety and tolerability were acceptable. Active metabolite M2 plasma concentration was reached rapidly and maintained for 3 to 4 days in all cases and more than 80% of the subjects had pre-dose plasma levels above 10 mg/L.
Conclusions: Based on these results, the dosing regimen of phase II study was defined and is about to be tested.