Penetration of dimethyl fumarate into cerebrospinal fluid and brain: a pharmacokinetic and tissue distribution study in monkeys
Author(s):
N. Penner
,
N. Penner
Affiliations:
B. Zhu
,
B. Zhu
Affiliations:
C. Woodward
,
C. Woodward
Affiliations:
M. Rogge
M. Rogge
Affiliations:
ECTRIMS Online Library. Penner N. 09/15/16; 146512; P672
Natalia Penner
Natalia Penner
Contributions
Abstract

Abstract: P672

Type: Poster

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. Studies of DMF in rats and mice suggested DMF and its metabolites penetrate into central nervous system (CNS), however, pharmacokinetics of CNS penetration in monkeys, the most relevant model for clinical translation, have not been studied.

Objectives: To investigate the pharmacokinetics of monomethyl fumarate (MMF) in plasma and cerebrospinal fluid (CSF), and tissue distribution of DMF and its metabolites in brain and spinal cord of monkeys.

Methods: Four cynomolgus monkeys were dosed intra-duodenally with 14C-DMF (25 mg/kg). Plasma and lumbar CSF samples were collected at pre-dose and then at 0.5, 1, 1.5, 2, 4, and 6 h post-dose. Tissue distribution in the CNS was examined at 2 and 4 h by quantitative whole-body autoradiography.

Results: Consistent with previous findings, DMF was not detected in plasma or CSF samples at any time point. Monomethyl fumarate (MMF) was detected in all collected samples as a major metabolite of DMF. Glutathione conjugates of DMF and MMF were minor in plasma and CSF. For MMF, plasma Tmax occurred at 0.5 hours post-dose, while CSF Tmax was delayed to 1.5 h post-dose. Total radioactivity profile was similar, with Tmax in plasma and CSF at 1 and 2 h, respectively. At CSF Cmax, CSF concentrations of MMF and total radioactivity were on average 15% and 30% of plasma concentration. In the terminal phase (3-6 h), the ratio increased to ~40% for both. The highest concentration of DMF-radioactivity in CNS tissues was observed in the frontal lobe cortex, the basal ganglia and thalamus; levels in white matter, optic nerve and spinal cord were 2-3-fold lower. It was shown that DMF-derived radioactivity in CNS is largely bound to tissues.

Conclusions: DMF-derived radioactivity and MMF penetrate into CNS tissues and CSF of monkeys after an oral dose of DMF.

Disclosure: Supported by: Biogen

Natalia Penner: employee of and holds stock/stock options in Biogen

Bing Zhu: employee of and holds stock/stock options in Biogen

Caroline Woodward: employee of and holds stock/stock options in Biogen

Mark Rogge: employee of and holds stock/stock options in Biogen

Abstract: P672

Type: Poster

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. Studies of DMF in rats and mice suggested DMF and its metabolites penetrate into central nervous system (CNS), however, pharmacokinetics of CNS penetration in monkeys, the most relevant model for clinical translation, have not been studied.

Objectives: To investigate the pharmacokinetics of monomethyl fumarate (MMF) in plasma and cerebrospinal fluid (CSF), and tissue distribution of DMF and its metabolites in brain and spinal cord of monkeys.

Methods: Four cynomolgus monkeys were dosed intra-duodenally with 14C-DMF (25 mg/kg). Plasma and lumbar CSF samples were collected at pre-dose and then at 0.5, 1, 1.5, 2, 4, and 6 h post-dose. Tissue distribution in the CNS was examined at 2 and 4 h by quantitative whole-body autoradiography.

Results: Consistent with previous findings, DMF was not detected in plasma or CSF samples at any time point. Monomethyl fumarate (MMF) was detected in all collected samples as a major metabolite of DMF. Glutathione conjugates of DMF and MMF were minor in plasma and CSF. For MMF, plasma Tmax occurred at 0.5 hours post-dose, while CSF Tmax was delayed to 1.5 h post-dose. Total radioactivity profile was similar, with Tmax in plasma and CSF at 1 and 2 h, respectively. At CSF Cmax, CSF concentrations of MMF and total radioactivity were on average 15% and 30% of plasma concentration. In the terminal phase (3-6 h), the ratio increased to ~40% for both. The highest concentration of DMF-radioactivity in CNS tissues was observed in the frontal lobe cortex, the basal ganglia and thalamus; levels in white matter, optic nerve and spinal cord were 2-3-fold lower. It was shown that DMF-derived radioactivity in CNS is largely bound to tissues.

Conclusions: DMF-derived radioactivity and MMF penetrate into CNS tissues and CSF of monkeys after an oral dose of DMF.

Disclosure: Supported by: Biogen

Natalia Penner: employee of and holds stock/stock options in Biogen

Bing Zhu: employee of and holds stock/stock options in Biogen

Caroline Woodward: employee of and holds stock/stock options in Biogen

Mark Rogge: employee of and holds stock/stock options in Biogen

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