Abstract
Objective: Pharmacokinetic evaluation of Dimethyl Fumarate (DMF) in the Iranian population wasn’t studied. So, the aim of this research is the validation of the analytical method and evaluation of the pharmacokinetic properties and bioequivalence of the generic form of this drug versus the reference product. Methods: 2 single-dose, test, and reference DMF products were orally administered to 24 healthy volunteers. The washout period was 28 d between the treatments. Monomethyl fumarate as the metabolite of DMF was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the method was validated. Also, the pharmacokinetic parameters were calculated for bioequivalence evaluation. Results: The analytical method was validated and linear over the range of 31.25-4000 ng/ml (R2= 0.997). In addition, the method was precise and accurate in the low, medium, and high concentrations. The results indicated that the 2 products had similar pharmacokinetics. Further, the 90% CI of the mean ratios of the test versus the reference products of the log-transformed area under the concentration-time curve over 10 h (0.99 to 1.02) and peak concentration (0.98 to 1.03) were within the acceptable range of 0.8 to 1.25 and the generic product of DMF could be similar to that of the reference product. Conclusion: The applied analytical method is selective, accurate, precise, and repeatable for the analysis of monomethyl fumarate (MMF) in plasma. Also, the bioequivalence study showed no significant difference between the pharmacokinetic parameters of these 2 products. So, the DMF test product can be claimed to be bioequivalent with the reference product.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the central nervous system (CNS) [1] that attacks and destroyed the myelinated axons [2]
Dimethyl fumarate (DMF) was approved for the treatment of psoriasis in 1959 [7] and got approved under the brand name of Tecfidera® for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS) in 2013 [8]
DMF may cause anti-inflammatory and cytoprotective activities that are mediated by the nuclear factor-like 2 (Nrf2) antioxidant response pathway [9]
Summary
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the central nervous system (CNS) [1] that attacks and destroyed the myelinated axons [2]. Most of the MS patients (80–85%) have a Relapsing-Remitting Multiple Sclerosis (RRMS) disease form [3]. Treatment options in RRMS have increased to a dozen different available disease-modifying medicines and a few more are expected to be marketed soon [4]. Dimethyl fumarate (DMF), known as BG-12, is the first-line oral treatment for RRMS [5] and has immunomodulatory properties [6]. DMF was approved for the treatment of psoriasis in 1959 [7] and got approved under the brand name of Tecfidera® for the treatment of RRMS in 2013 [8]. DMF may cause anti-inflammatory and cytoprotective activities that are mediated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway [9]
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