Comparative pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of Bafiertam? (monomethyl fumarate) versus Vumerity? (diroximel fumarate)

Background: Bafiertam (R) (monomethyl fumarate [MMF]) and Vumerity (R) (diroximel fumarate [DRF]) are two FDA approved drug products for the treatment of relapsing forms of multiple sclerosis (MS) to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Vumerity (R) is a prodrug of MMF which requires enzymatic conversion of DRF to the active drug MMF, the moiety responsible for the therapeutic efficacy; whereas Bafiertam (R) contains MMF, providing the active drug directly without any need for enzymatic conversion.Objective: The objective of this study was to evaluate the pharmacokinetics and relative bioavailability of MMF from oral administration of two Bafiertam (R) capsules each containing 95 mg of MMF in comparison to two Vumerity (R) capsules each containing 231 mg of DRF, the therapeutic doses of each product.Methods: This was a single-dose, open-label, randomized, 2-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Forty-four healthy male or female subjects were planned to receive each of the two treatments to assure 40 completed dosing: a single dose of 2 x 95 mg Bafiertam (R) capsules and a single dose of 2 x 231 mg Vumerity (R) capsules under fasting conditions in a randomized crossover fashion. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. MMF pharmacokinetic [PK] parameters were calculated and included maximum observed concentration (Cmax), time to reach Cmax (tmax), apparent half-life of MMF in plasma (t1/2), AUC0-t which is the area under the plasma concentration vs. time curve (AUC) from time zero (dosing time) to the last time point, t, with quantifiable MMF concentration, and AUC0-inf which is AUC0-t plus the extrapolated AUC from time t to infinity.Results: Forty-one subjects completed the study as planned. MMF in Bafiertam (R) capsules was well and readily absorbed with a median tmax occurring at 4 h post dose, approximately 1 h later than that of Vumerity (R) capsules. However, the mean MMF Cmax from Bafiertam (R) (1969 ng/mL) was higher than that from Vumerity (R) (1121 ng/mL). The mean MMF AUC0-t and AUC0-inf from Bafiertam (R) (3503 and 3531 h*ng/mL) were also higher than those from Vumerity (R) (3123 and 3227 h*ng/mL), respectively. The geometric least-squares mean (GLSM) ratios (90% confidence interval), Bafiertam (R) vs. Vumerity (R), for MMF Cmax,AUC0-t and AUC0-inf were 181.8 (158.2 -208.8)%, 116.8 (107.9-126.5)% and 113.8 (105.3 -123.0)%, respectively. Both products were safe and well tolerated, as expected, with flushing being the most common adverse event for both products.Conclusions: The mean MMF AUC0-t and AUC0-inf were 14-17% higher after administration of Bafiertam (R) as compared to Vumerity (R) at their respective therapeutic doses under fasting conditions, however, this difference was not statistically or clinically significant. Although more clinical studies would be needed before making strong recommendations, results of this study may help with selecting appropriate fumarate products, especially when administering the product with food is clinically recommended.