Determination of the dose proportionality of single intravenous doses (5, 10, and 15 mg) of lubeluzole in healthy volunteers.

The dose proportionality of lubeluzole, a drug in clinical development for the treatment of acute ischemic stroke, was evaluated in a Phase I, single-center, open-label, randomized-dosing-sequence, three-way crossover clinical trial in 12 healthy adults. An equal number of male and female volunteers were enrolled in the trial, with a mean weight (+/- SD) of 73.2 +/- 11.9 kg, mean height (+/- SD) of 66.8 +/- 4.6 inches, and a mean age of 36.1 +/- 5.2 years. Subjects received intravenous infusions of 5 (A), 10 (B), and 15 mg (C) of lubeluzole over 1 hour on three separate occasions, with a minimum washout period of 2 weeks. The treatment sequences were A-B-C; A-C-B; B-A-C; B-C-A; C-A-B; and C-B-A. One male and one female were assigned to each sequence. After the 5-, 10-, and 15-mg doses, maximum concentration (Cmax) was 58.1, 113, and 138 microg/L, respectively, and the area under the curve from 0 to (AUC(0-infinity)) was 771, 1384, and 2025 microg x h/L. There were no statistically significant differences among the groups in mean terminal half-life, steady-state volume of distribution, total plasma clearance, or dose-normalized AUC(0-infinity). Dose-normalized values of Cmax differed significantly between the groups. No serious adverse events were reported, and no changes were observed in cardiac function, as judged by the QT(c) interval. The pharmacokinetics of lubeluzole appear to be linear at intravenous infusion doses of 5, 10, and 15 mg, and these doses are well tolerated by healthy adults.