Safety, Tolerability and Pharmacokinetics of MCI-186 in Patients with Acute Ischemic Stroke: New Formulation and Dosing Regimen

Abstract

Background and Purpose: MCI-186 (edaravone) is a free radical scavenger approved in Japan since 2001 for the treatment of patients with acute ischemic stroke within 24 h from the onset of symptoms. It was recommended by the Japanese Guidelines for the Management of Stroke 2004. Our aim was to investigate the safety, tolerability and pharmacokinetics of a new formulation and dose regimen (intravenous bolus plus infusion) of MCI-186 suitable for the treatment of acute ischemic stroke in Europe because the Japanese treatment protocol includes twice-a-day intravenous infusion of MCI-186 for a maximum of 14 days. Such a treatment protocol is not very practical in Europe, where hospital stay is much shorter in acute hospitals. Methods: In a double-blind, placebo-controlled randomized clinical trial we studied two dosing regimens, each in a cohort of 18 patients. Patients were randomized in a 2:1 ratio in both cohorts to receive MCI-186 or placebo. Review of safety and plasma concentration data from the first cohort (loading dose 0.08 mg/kg + 0.2 mg/kg/h infusion) preceded the second cohort (loading dose 0.16 mg/kg + 0.4 mg/kg/h infusion). Safety parameters included adverse events, severe adverse events, physical examinations, local reactions at infusion site, ECG, clinical chemistry and hematology, modified Total Neuropathy Score and CT scans. Results: Mean age and National Institutes of Health Stroke Scale (NIHSS) score on admission of patients in cohorts 1 and 2 and the placebo group were 64, 63, and 69 years and 5, 5, and 6, respectively. The number of treatment emergent adverse events that occurred was 109, most of which were transient, mild or moderate. Both doses of the new formulation and dosing regimen were well tolerated. After the initiation of the infusion, plasma concentrations of MCI-186 reached or exceeded prespecified target levels within 24 h in both MCI-186 cohorts, which were in the putative therapeutic range in humans. Geometric mean values of MCI-186 plasma concentration at the end of the infusion in cohorts 1 and 2 were 391 and 1,595 ng/ml, respectively. Conclusions: The primary objective of the present study, safety and tolerability of the new formulation and dosing regimen, was achieved. The new formula and both dosing regimens were well tolerated and achieved intended plasma concentrations suitable for larger safety studies before pivotal trials.

Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

“…The edaravone concentrations used were in the millimolar range similarly to another independent work on cultured human brain endothelial cells. For long-lasting protection suprapharmacological concentration of edaravone [66] was needed in our culture study. However, the applied methylglyoxal levels were also comparably high, as in other in vitro methylglyoxal studies [25], [28], [37], [53].…”

Prophylactic Edaravone Prevents Transient Hypoxic-Ischemic Brain Injury

“…Clinically, Edaravone is used in Japan to treat acute ischemic stroke with a two-week, twice-a-day regimen 15 . A recent clinical trial in Europe shows that a shorter course of higher-dose Edaravone is also safe, tolerated, and improving the neurological outcome in ischemic stroke patients (although this study was not designed to determine efficacy) 16 . Finally, the combinational tPA-Edaravone treatment provides synergistic benefits of reduced infarct size in animal models and an increased recanalization rate for patients 9,17 .…”

“…It has been used for treating acute ischemic stroke in Japan since 2001 and is in clinical trials in Europe 15,16 . When combined with tissue-type plasminogen activator (tPA), Edaravone confers synergistic benefits in both animal models (reduction of the mortality and infarct size) and stroke patients (a greater recanalization rate) 9,17 .…”

Synergy of Combined tPA-Edaravone Therapy in Experimental Thrombotic Stroke

“…Edaravone has been approved for treating acute cerebral ischemia in Japan since 2001, but its worldwide clinical development is still in its infancy [29], [36]. Edaravone is a lipophilic free radical scavenger that neutralizes multiple reactive oxygen species and protects both neurons and endothelial cells in the neurovascular unit [24], [37].…”