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- Title
Development of a Population Pharmacokinetic Model for the Diroximel Fumarate Metabolites Monomethyl Fumarate and 2-Hydroxyethyl Succinimide Following Oral Administration of Diroximel Fumarate in Healthy Participants and Patients with Multiple Sclerosis.
- Authors
Kuchimanchi, Mita; Bockbrader, Howard; Dolphin, Nancy; Epling, Daniel; Quinlan, Lauren; Chapel, Sunny; Penner, Natasha
- Abstract
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.
- Subjects
SUCCINIMIDES; MULTIPLE sclerosis; PHARMACOKINETICS; METABOLITES; ASPARTATE aminotransferase
- Publication
Neurology & Therapy, 2022, Vol 11, Issue 1, p353
- ISSN
2193-8253
- Publication type
Article
- DOI
10.1007/s40120-021-00316-6