Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study

Abstract

Background and purpose: Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke.

Methods: Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days.

Results: Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses.

Conclusions: Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Conflict of interest statement

Conflicts of Interest/ Disclosures

SCF: grant support/ consultant to Pfizer, Inc; consultant to Ferrer, grant support from VA Merit Review, NINDS (RO1 NS063965)

LCP: consultant for Genesis Biopharma; grant support from VA Merit Review

JAS: nothing to disclose

CEH: grant support: Actelion, NINDS; REACH co-founder

AE: grant support from VA Merit Review, AHA Established Investigator (EIA0740002N), NIH (RO1DK074385)

DCH: Speaker for Genentech, Boehringer Ingelheim; consultant for Ferrer; CoFounder REACH CALL, Inc

Figures

Figure

Average minocycline serum concentrations over time in the 3 and 10 mg/kg dose group (n=12). Only patients with complete data out to 48 hours were included. Peak concentrations after the last dose declined in a log-linear manner with a half-life of approximately 24 hours.