title: Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers.
abstract: BACKGROUND
  Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.
  
  
  METHODS
  Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.
  
  
  RESULTS
  DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0-10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF-treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.
  
  
  CONCLUSIONS
  In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
authors.affiliation: Clinical Development, Biogen Idec Inc, Cambridge, Massachusetts. Electronic address: sarah.sheikh@biogenidec.com.
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Sheikh
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Heidy
authors.initials: H
authors.lastname: Russell
authors.forename: John
authors.initials: J
authors.lastname: O'Gorman
authors.forename: Ron
authors.initials: R
authors.lastname: Huang
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Mark
authors.initials: M
authors.lastname: Novas
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Dawson
mesh_terms: D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001241:Aspirin / Q000008:administration & dosage*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D004064:Digestive System / Q000187:drug effects; D000069462:Dimethyl Fumarate; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005483:Flushing / Q000139:chemically induced; D005650:Fumarates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D005650:Fumarates; D000069462:Dimethyl Fumarate; D001241:Aspirin
keywords: dimethyl fumarate; flushing; multiple sclerosis; prostaglandin D(2)