RESUMEN
INTRODUCTION: Diroximel fumarate (DRF) is a next-generation oral fumarate that is indicated in the USA for relapsing forms of multiple sclerosis (MS). A joint population pharmacokinetic model was developed for the major active metabolite (monomethyl fumarate, MMF) and the major inactive metabolite (2-hydroxyethyl succinimide, HES) of DRF. METHODS: MMF and HES data were included from 341 healthy volunteers and 48 patients with MS across 11 phase I and III studies in which DRF was administered as single or multiple doses. Population modeling was performed with NONMEM version 7.3 with the first-order conditional estimation method. RESULTS: Estimated MMF clearance (CLMMF), volume of distribution, and absorption rate constant (Ka) were 13.5 L/h, 30.4 L, and 5.04 h-1, respectively. CLMMF and HES clearance (CLHES) increased with increasing body weight. CLHES decreased with decreasing renal function. CLMMF and CLHES were 28% and 12% lower in patients with MS than in healthy volunteers, respectively. Ka was reduced in the presence of low-, medium-, and high-fat meals by 37%, 51%, and 67%, respectively, for MMF; and by 34%, 49%, and 62%, respectively, for HES. CONCLUSIONS: Age, sex, race, and baseline liver function parameters such as total bilirubin, albumin, and aspartate aminotransferase were not considered to be significant predictors of MMF or HES disposition.