Safety, tolerability and pharmacokinetics of MCI-186 in patients with acute ischemic stroke: new formulation and dosing regimen.
Kaste M., Murayama S., Ford GA., Dippel DWJ., Walters MR., Tatlisumak T., MCI-186 study group None.
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.