Remimazolam: New Beginnings or Just a Me-Too?

This edition of the Journal includes 2 studies describing the first human administration of remimazolam, a novel benzodiazepine. Not all such Phase 1 studies have a happy ending; the dropout rate of development drugs is high and Phase 1 studies frequently represent the last outing for candidate compounds. Such investigations, together with early clinical studies, also offer the editorialist an opportunity to pontificate (often wrongly) on the possible advantages of the new drug and to indulge in some speculation. Hence: “mivacurium may constitute a versatile new addition to anesthetic practice,” “minaxolone is a most promising induction agent ...,” and more accurately, “midazolam would appear to offer many advantages over available benzodiazepines.” Can we improve on midazolam? Midazolam replaced diazepam because it is water soluble and does not cause pain on injection. Midazolam also has rapid onset and frequently induces amnesia. However, midazolam has an active metabolite, -hydroxy-midazolam, which is a potent sedative and contributes materially to the effects of its parent. After the introduction of midazolam, there were further efforts to identify short-acting benzodiazepines with rapid onset and offset. Ro 48-6791 had a similar speed of onset and duration of action to midazolam but was 3 to 6 times more potent. Recovery from Ro 48-8684 was faster than from midazolam. Neither compound was thought to have sufficient advantages over midazolam to merit further development. Why then bother with remimazolam? The answer is a matter of degree. Incorporation of an ester linkage into remimazolam permits hydrolysis by tissue esterases to an apparently inactive metabolite. Tissue esterases are diverse and ubiquitous; there is no deficiency condition. Furthermore, their capacity gives a high clearance with consequent rapid diminution of drug effect when administration is ceased. This approach works well for remifentanil and the experimental compounds MOC-etomidate and THRX-918661 (a propanidid derivative). Preclinical investigations in sheep showed remimazolam to produce dose-dependent sedation with a faster offset than midazolam. Remimazolam seems to be a substantial improvement on midazolam with an apparently inactive metabolite and a context-sensitive half-time plot reminiscent of that for remifentanil. What should we expect from a Phase 1 study? Regulators, such as the Food and Drug Administration, require the demonstration of safety and efficacy. In the world of clinical trials, these carry slightly different meanings to “real-world” clinical practice. Safety is quantified by adverse events and serious adverse events at the time of drug administration and for a few days afterward. Efficacy in Phase 1 may be no more than a simple observation that the compound has some effect in the desired indication. Recently, the increasing costs of clinical studies and pressure to accelerate development timetables (against a ticking patent clock) motivate sponsors to bring forward into Phase 1 active comparators (in this case midazolam) and detailed attempts to compare the new drug with the old. This is not necessarily a bad thing because the science is thereby enriched although excessive measurements (end points) may overcomplicate the study design. Another important objective in Phase 1 is to explore the whole of the dose-response curve ranging from a “no effect” dose to doses at which adverse effects begin to occur. Failing to do this in Phase 1 may otherwise lead to surprises later in clinical development. The first human study of remimazolam appropriately explores the entire spectrum of drug effect, permits comparison with the current “gold standard,” midazolam, and through detailed pharmacokinetic/pharmacodynamic modeling, adds numbers to qualitative descriptions of differences and permits exploration through simulation of alternative schedules of remimazolam administration. How did remimazolam fare in this investigation? Remimazolam produces rapid-onset dose-related sedation that is qualitatively similar to that produced by midazolam but of substantially shorter duration. The profile of adverse events suggests that the new compound is relatively “clean” and remimazolam seems (so far) to be a “typical” benzodiazepine. How is this achieved? Remimazolam is built on a typical benzodiazepine structure and binds to benzodiazepine receptors with reversal by flumazenil. Pharmacokinetic modeling reveals remimazolam to have a higher clearance and smaller volume of distribution than midazolam; these explain the rapid offset of drug effect after short-term administration. An important limitation on Phase 1 volunteer studies is the gender mix (typically all male or mostly male), limited age range, and prospective selection for general good health of the subjects. The population is therefore relatively From Plymouth University Peninsula Schools of Medicine and Dentistry, United Kingdom.