Contributions
Abstract: EP1501
Type: ePoster
Abstract Category: Therapy - disease modifying - Neuroprotection
Background: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) has been approved for the treatment of patients with relapsing multiple sclerosis (MS) or relapsing remitting MS. While the mechanisms underlying disease progression in MS remain unclear, evidence suggests that the pathogenesis of MS involves inflammation-driven oxidative injury in the central nervous system (CNS). Pharmacokinetic studies in rodents suggest that monomethyl fumarate (MMF), the primary and measurable metabolite of DMF, penetrates into the brain and cerebrospinal fluid (CSF). The CSF levels of MMF in humans after DMF treatment have not been evaluated.
Objectives: To investigate the pharmacokinetics of MMF in plasma and CSF after oral administration of DMF in subjects with SPMS.
Methods: Sixteen SPMS patients with no prior DMF exposure were recruited to take oral DMF 120 mg twice daily (BID) for 4 weeks, followed by DMF 240 mg BID for 24 weeks. During Week 6 (the second week on DMF 240 mg), plasma samples were collected before the morning dose and then at 2, 3, 5, 6, 7, 8 and 10 hours post morning dose. In addition, CSF samples were collected at 3, 5, or 7 hours post-dose (4 patients at each time point), at 10 hours post-dose (3 patients). MMF concentrations in plasma and CSF samples were determined by liquid chromatography and mass spectrometry.
Results: Median time to peak plasma MMF concentration (Tmax) was 5 hours post-dose with maximum concentrations (Cmax) ranging from 1140-3560 ng/mL. Highest CSF level of MMF was at 7 hours post-dose with maximal CSF concentration of 39-79 ng/ml. At 7 hours post-dose, on average, the ratio of CSF to plasma concentrations of MMF was 15%.
Conclusions: This study shows that MMF penetrates into CNS as measured by its level in CSF in SPMS patients.
Disclosure: Supported by an unrestricted educational grant from Biogen.
Keith R. Edwards: Consulting and/or Speaking fees: Biogen, Genzyme; EMD Serono; Grant/Research support: Biogen, Eisai, Eli Lilly, Genentech, Genzyme/Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis
Natasha Penner: employee of and holds stock/stock options in Biogen
Mark Rogge: employee of and holds stock/stock options in Biogen
Sarah Sheikh: employee of and holds stock/stock options in Biogen
Bing Zhu: employee of and holds stock/stock options in Biogen
Abstract: EP1501
Type: ePoster
Abstract Category: Therapy - disease modifying - Neuroprotection
Background: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) has been approved for the treatment of patients with relapsing multiple sclerosis (MS) or relapsing remitting MS. While the mechanisms underlying disease progression in MS remain unclear, evidence suggests that the pathogenesis of MS involves inflammation-driven oxidative injury in the central nervous system (CNS). Pharmacokinetic studies in rodents suggest that monomethyl fumarate (MMF), the primary and measurable metabolite of DMF, penetrates into the brain and cerebrospinal fluid (CSF). The CSF levels of MMF in humans after DMF treatment have not been evaluated.
Objectives: To investigate the pharmacokinetics of MMF in plasma and CSF after oral administration of DMF in subjects with SPMS.
Methods: Sixteen SPMS patients with no prior DMF exposure were recruited to take oral DMF 120 mg twice daily (BID) for 4 weeks, followed by DMF 240 mg BID for 24 weeks. During Week 6 (the second week on DMF 240 mg), plasma samples were collected before the morning dose and then at 2, 3, 5, 6, 7, 8 and 10 hours post morning dose. In addition, CSF samples were collected at 3, 5, or 7 hours post-dose (4 patients at each time point), at 10 hours post-dose (3 patients). MMF concentrations in plasma and CSF samples were determined by liquid chromatography and mass spectrometry.
Results: Median time to peak plasma MMF concentration (Tmax) was 5 hours post-dose with maximum concentrations (Cmax) ranging from 1140-3560 ng/mL. Highest CSF level of MMF was at 7 hours post-dose with maximal CSF concentration of 39-79 ng/ml. At 7 hours post-dose, on average, the ratio of CSF to plasma concentrations of MMF was 15%.
Conclusions: This study shows that MMF penetrates into CNS as measured by its level in CSF in SPMS patients.
Disclosure: Supported by an unrestricted educational grant from Biogen.
Keith R. Edwards: Consulting and/or Speaking fees: Biogen, Genzyme; EMD Serono; Grant/Research support: Biogen, Eisai, Eli Lilly, Genentech, Genzyme/Sanofi, Hoffmann-La Roche, Merz Pharmaceuticals, Novartis
Natasha Penner: employee of and holds stock/stock options in Biogen
Mark Rogge: employee of and holds stock/stock options in Biogen
Sarah Sheikh: employee of and holds stock/stock options in Biogen
Bing Zhu: employee of and holds stock/stock options in Biogen