Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers

Clinical Therapeutics

Volumn 35, Issue 10, 2013, Pages

  Sheikh, Sarah I ^a   Nestorov, Ivan ^a   Russell, Heidy ^b   O'Gorman, John ^b   Huang, Ron ^a   Milne, Ginger L ^c   Scannevin, Robert H ^a   Novas, Mark ^a   Dawson, Katherine T ^a  

^a BIOGEN   (United States)

^b PROMETRIKA LLC   (United States)

^c VANDERBILT UNIVERSITY   (United States)

Author keywords

Dimethyl fumarate; Flushing; Multiple sclerosis

Indexed keywords

ACETYLSALICYLIC ACID; FUMARIC ACID DIMETHYL ESTER; FUMARIC ACID METHYL ESTER; PLACEBO; PROSTAGLANDIN D2;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLOATING; CONTROLLED STUDY; DELAYED RELEASE FORMULATION; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; HUMAN; MALE; METABOLITE; NAUSEA; NORMAL HUMAN; RANDOMIZED CONTROLLED TRIAL; RATING SCALE; STOMACH PAIN; VOMITING;

DIMETHYL FUMARATE; FLUSHING; MULTIPLE SCLEROSIS; PROSTAGLANDIN D(2);

ADOLESCENT; ADULT; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ASPIRIN; CYCLOOXYGENASE INHIBITORS; DELAYED-ACTION PREPARATIONS; DIGESTIVE SYSTEM; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG THERAPY, COMBINATION; FEMALE; FLUSHING; FUMARATES; HEALTHY VOLUNTEERS; HUMANS; MALE; MIDDLE AGED; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84885791170     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2013.08.009     Document Type: Article

References (24)

1. Tecfidera T.M. [US Prescribing Information] 2013, Biogen Idec Inc, Cambridge, MA, USA.
2. Dutta R., Trapp B.D. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 2011, 93:1-12.
3. Gilgun-Sherki Y., Melamed E., Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 2004, 251:261-268.
4. Nguyen T., Sherratt P.J., Pickett C.B. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003, 43:233-260.
5. Baird L., Dinkova-Kostova A.T. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 2011, 85:241-272.
6. Fox R.J., Miller D.H., Phillips J.T., et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012, 367:1087-1097.
7. Gold R., Kappos L., Arnold D., et al. Placebo-controlled Phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012, 367:1098-1107.
8. Morrow J.D., Parsons W.G., Roberts L.J. Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins 1989, 38:263-274.
9. Plummer N.A., Hensby C.N., Black A.K., et al. Prostaglandin activity in sustained inflammation of human skin before and after aspirin. Clin Sci Mol Med 1977, 52:615-620.
10. Maintz L., Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007, 85:1185-1196.
11. Morrow J.D., Awad J.A., Oates J.A., et al. Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol 1992, 98:812-815.
12. Papaliodis D., Boucher W., Kempuraj D., et al. Niacin-induced "flush" involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model. J Pharmacol Exp Ther 2008, 327:665-672.
13. Stern R.H., Spence J.D., Freeman D.J., et al. Tolerance to nicotinic acid flushing. Clin Pharmacol Ther 1991, 50:66-70.
14. Benyo Z., Gille A., Bennett C.L., et al. Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells. Mol Pharmacol 2006, 70:1844-1849.
15. Maciejewski-Lenoir D., Richman J.G., Hakak Y., et al. Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol 2006, 126:2637-2646.
16. Benyo Z., Gille A., Kero J., et al. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest 2005, 115:3634-3640.
17. Hanson J., Gille A., Zwykiel S., et al. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest 2010, 120:2910-2919.
18. Paolini J.F., Mitchel Y.B., Reyes R., et al. Measuring flushing symptoms with extended-release niacin using the flushing symptom questionnaire: results from a randomised placebo-controlled clinical trial. Int J Clin Pract 2008, 62:896-904.
19. Norquist J.M., Watson D.J., Yu Q., et al. Validation of a questionnaire to assess niacin-induced cutaneous flushing. Curr Med Res Opin 2007, 23:1549-1560.
20. Lai E., De L., I, Crumley T.M., et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther 2007, 81:849-857.
21. Milne G.L., Sanchez S.C., Musiek E.S., et al. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nat Protoc 2007, 2:221-226.
22. Awad J.A., Morrow J.D., Roberts L.J. Simplification of the mass spectrometric assay for the major urinary metabolite of prostaglandin D2. J Chromatogr 1993, 617:124-128.
23. Woodworth J, Zhao J, Stecher S, et al. Oral BG-12 in combination with interferon beta-1a or glatiramer acetate: pharmacokinetics, safety and tolerability. Poster P478 presented at: European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS]; October 13-16, 2010; Gothenburg, Sweden.
24. Kappos L., Gold R., Miller D.H., et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008, 372:1463-1472.