A Placebo- and Midazolam-Controlled Phase I Single Ascending-Dose Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Remimazolam (CNS 7056)

BACKGROUND: A new benzodiazepine, remimazolam, metabolized by tissue esterases to an inactive compound, CNS 7054, has been developed to permit a fast onset, a short and more predictable duration of sedative action, and a more rapid recovery profile than with currently available benzodiazepines. We report on the safety and efficacy of the first human study. METHODS: A phase I, single-center, double-blind, placebo- and active-controlled, randomized, single-dose escalation study was conducted. Up to 10 cohorts of healthy subjects were scheduled to receive a single 1-minute IV infusion of remimazolam, midazolam, or placebo. In the 10 possible cohorts, remimazolam doses were from 0.01 to 0.35 mg/kg. In cohorts 1 to 3, 6 subjects received remimazolam and 1 placebo. From cohort 4 onward, an additional 3 subjects in each cohort received midazolam (0.075 mg/kg). Safety, pharmacokinetics, and pharmacodynamics were measured. A stop criterion of loss of consciousness for >5 minutes in >50% of subjects was predefined. RESULTS: The stop criterion was reached in cohort 9 (0.30 mg/kg remimazolam) so that 81 subjects were enrolled. Remimazolam was well tolerated in all dose cohorts, and no serious adverse events (AEs) were reported. Three AEs of mild (Spo(2) 85%-88%) hemoglobin desaturation (2 in the remimazolam groups and 1 in the midazolam group) resolved spontaneously, and 1 AE of moderate hemoglobin desaturation (Spo(2) 75%) resolved with a chin lift in the highest remimazolam dose group. No supplemental oxygen or manual ventilation was required. Vital signs remained stable throughout, although there was an increase in heart rate 2 minutes postdose for both remimazolam and midazolam. There were no reports of hypo- or hypertension. The pharmacokinetic behavior of remimazolam was linear and its systemic clearance approximately 3 times that of midazolam. Clearance was essentially independent of body weight. A rapid onset and dose-dependent sedation was observed after administration of remimazolam at 0.05 mg/kg and higher. Remimazolam (0.075 to 0.20 mg/kg) induced peak sedation levels similar to or higher than those achieved with midazolam (0.075 mg/kg). Median recovery times after approximately equieffective doses of remimazolam (0.10 and 0.15 mg/kg) and midazolam (0.075 mg/kg) were 10 and 40 minutes, respectively. CONCLUSIONS: Remimazolam provided sedation with rapid onset and offset, and was well tolerated. There was no supplemental oxygen or ventilation required. On the basis of these data, further studies on the potential utility of remimazolam for sedation/anesthesia are warranted.