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

BACKGROUND: Bafiertam® (monomethyl fumarate [MMF]) and Vumerity® (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® 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® 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® capsules each containing 95 mg of MMF in comparison to two Vumerity® 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  ×  95 mg Bafiertam® capsules and a single dose of 2  ×  231 mg Vumerity® 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® capsules was well and readily absorbed with a median tmax occurring at 4 h post dose, approximately 1 h later than that of Vumerity® capsules. However, the mean MMF Cmax from Bafiertam® (1969 ng/mL) was higher than that from Vumerity® (1121 ng/mL). The mean MMF AUC0-t and AUC0-inf from Bafiertam® (3503 and 3531 h*ng/mL) were also higher than those from Vumerity® (3123 and 3227 h*ng/mL), respectively. The geometric least-squares mean (GLSM) ratios (90% confidence interval), Bafiertam® vs. Vumerity®, 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® as compared to Vumerity® 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.

Efficacy and Safety of Alemtuzumab in Patients of African Descent with Relapsing-Remitting Multiple Sclerosis: 8-Year Follow-up of CARE-MS I and II (TOPAZ Study).

INTRODUCTION: Multiple sclerosis (MS) patients of African descent have increased risk for disease progression and may be less responsive to disease-modifying therapy. METHODS: Patients in the CARE-MS studies received alemtuzumab 12 mg/day [initial alemtuzumab treatment (IAT); baseline: 5 days; 12 months later: 3 days] or subcutaneous interferon beta-1a (SC IFNB-1a) 3 ×/week. Core study outcomes were compared between treatment groups. In the extension study CAMMS03409, SC IFNB-1a-treated patients switched to alemtuzumab [delayed alemtuzumab treatment (DAT)]. Data from IAT and DAT arms were pooled to assess outcomes through 6 years post alemtuzumab initiation; IAT patients had an additional 2 years of follow-up in TOPAZ. RESULTS: Of 1200 CARE-MS patients, 43 (4%) were of African descent (35 IAT; 8 DAT) and received alemtuzumab in the 2-year core and/or 6-year extension; 29 (67%) remained on study at the time of analysis (24 IAT patients completed year 8 post alemtuzumab; 5 DAT patients completed year 6 post alemtuzumab). In year 2, annualized relapse rate (ARR; 0.09 versus 0.42), percentage of patients with improved Expanded Disability Status Scale (EDSS; 18% versus 11%), 6-month confirmed disability improvement (CDI; 28% versus 13%), no evidence of disease activity (55% versus 13%), and cumulative brain volume loss (BVL; - 0.55% versus - 1.32%) favored alemtuzumab versus SC IFNB-1a. Alemtuzumab remained efficacious at year 6 (pooled IAT/DAT) and at year 8 (IAT only) post alemtuzumab (ARR: 0.15 and 0.30; improved EDSS: 17% and 25%; CDI: 47% and 55%; BVL: - 1.14% and - 0.70%, respectively). No safety signals were unique to this population. CONCLUSIONS: Alemtuzumab was efficacious in a small cohort of relapsing-remitting MS patients of African descent over 8 years. Safety was consistent with the overall CARE-MS population, although the small sample size may have prevented the detection of known low-frequency adverse events. CLINICALTRIALS. GOV REGISTRATION NUMBERS: CARE-MS I, II, extension, TOPAZ: NCT00530348, NCT00548405, NCT00930553, NCT02255656. FUNDING: Sanofi (Cambridge, MA, USA) and Bayer HealthCare Pharmaceuticals (Leverkusen, Germany).

Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study.

OBJECTIVE: This study aimed to assess potential efficacy and safety of dextromethorphan/quinidine (DMQ) in prophylactic treatment of migraine in patients with multiple sclerosis (MS) with superimposed pseudobulbar affect (PBA). METHODS: Multiple sclerosis patients with superimposed PBA and comorbid migraine were enrolled into this open-label observational study at the University of Southern California Comprehensive MS Center. The baseline characteristics included, among other data, frequency and severity of acute migraine attacks and use of migraine relievers. The DMQ was used exclusively per its primary indication - PBA symptoms control - 20/10 mg orally, twice a day for the mean of 4.5 months (the shortest exposure registered was 3 months and the longest, 6 months). To determine whether treatment caused an effect on migraine frequency and severity, the baseline and posttreatment values were compared using nonparametric sign test. RESULTS: Thirty-three MS subjects with PBA, who also suffered from migraines, were identified. Twenty-nine subjects had improvement in headache frequency, 4 had no change, and none had worsening (P < 0.001 as compared with the baseline). Twenty-eight subjects had improvement in headache severity, 5 had no change, and none had worsening (P < 0.001). CONCLUSIONS: Our pilot study results provide evidence that DMQ shows promise as a candidate for larger clinical studies evaluating its efficacy for the prevention of migraine headaches.

Intravenous valproate inhibits ongoing and evoked activity of dura-sensitive thalamic neurons in rats.

Valproate is widely used for migraine treatments, although precise mechanisms of its anticephalgic action are poorly understood. Migraine attacks are thought to occur due to trigemino-vascular system activation, which in turn, stimulates nociceptive transmission in trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus of the thalamus is considered to play a prominent role in neurobiology of headaches by serving as the highest subcortical relay for conveying nociceptive information from intra- and extra-cranial structures to the cortex. While it has been demonstrated that valproate can modulate trigemino-vascular nociceptive neurotransmission in the VPM, its effects have been investigated using only intrathalamic ejection of the compound in pentobarbitone sodium anesthetized rats. The objective of our study was to evaluate the effects of intravenously administered valproate on both ongoing firing of the VPM neurons and their activity induced by electrical stimulation of the dura mater. The experiments were performed on rats under nonbarbiturate anesthesia. To define the dose-dependent properties and longevity of the studied effects of valproate, two distinguished dosing regiments were used: bolus (single infusion at a dose of 300 mg/kg) and cumulative (thrice-repeated administration of 100mg/kg performed 30 min apart). Intravenous administration of valproate produced the dose-dependent suppression of both the ongoing activity of the thalamic VPM neurons and their responses to electrical stimulation of the dura mater. This effect was fast-developing (within 5 min) and short-lasting (no longer than 30 min). These data suggest that intravenous administration of valproate could produce a reduction of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation.