A recent phase I clinical trial reported on the pharmacokinetics of remimazolam, a new benzodiazepine, in normal volunteers. Which of the following is MOST likely true about its characteristics compared to midazolam?
(A) Remimazolam has more rapid clearance.
(B) Remimazolam has slower onset.
(C) Remimazolam is less potent.
(D) Remimazolam is associated with fewer side effects.
A recent publication reported on the first phase I clinical trial of remimazolam in normal volunteers. Remimazolam is a novel benzodiazepine designed to undergo rapid hydrolysis to inactive metabolites. Like the similarly named remifentanil, remimazolam was designed to be administered by continuous infusion for easily titrated sedation in short surgical cases and procedures.
In this pharmacokinetic study, remimazolam was administered as an intravenous bolus at doses ranging from 0.05 mg/kg to 0.35 mg/kg. Depth of sedation, plasma clearance, and the occurrence of side effects were compared in a double-blind fashion to the known effective dose of midazolam (0.075 mg/kg) and to an inactive placebo. The dose of remimazolam was escalated steadily in successive groups of study patients until the majority of volunteers at the given dose required airway support to preserve ventilation.
Onset time of clinical sedation occurred within 60 seconds with either midazolam or remimazolam. Both the depth and duration of sedation with remimazolam were dose-dependent. Side effects were minimal for both drugs and similar to those experienced in the volunteers who received placebo. No volunteer in any group experienced hypotension. Volunteers in both the midazolam and remimazolam groups experienced a mild increase in heart rate at clinically significant levels of sedation.
The most important finding of this trial was a three-times greater clearance of remimazolam compared to midazolam. Remimazolam had a terminal phase half-life of about 45 minutes, which was unaffected by the dose given. By comparison, the half-life of midazolam was 4.3 hours. At the clinically effective dose of 0.075 mg/kg, most volunteers were fully conscious within 15 minutes of a bolus dose of remimazolam, but volunteers took more than 60 minutes to recover from the same dose of midazolam.
This phase I study of remimazolam suggests great promise for improving the safety of moderate and deep sedation. Further studies will be required before remimazolam is likely to be available in clinical practice, including phase II studies of safety and efficacy in actual patients, one or more large phase III trials, studies of interactions with other medications (especially narcotics), and pragmatic trials reflecting use in common clinical scenarios.
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• Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012;115(2):274–283.
• Reves JG, Glass PSA, Lubarsky DA, McEvoy MD, Martinez-Ruiz R. Intravenous anesthetics. In: Miller RD, ed. Miller’s Anesthesia. 7th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2010:734-741.