Remimazolam and Ciprofol: More Research Is Needed but Ask the Right Questions and Perhaps Aim Higher

The commercial sponsors of drug development, i.e., pharmaceutical companies, are quite properly interested in obtaining product licences for their compounds with a view to clinical sales. To this end, they must demonstrate that the development candidate is safe and efficacious as defined by well-developed but dynamic standards set by regulators. Done well, with extreme focus, this process may be relatively swift. Remifentanil went from patent to licensing in 7 yr, a process that was likely helped by a large and experienced sponsor (GSK Plc, London, United Kingdom), with a drug from a well-established chemical series (synthetic opioids: fentanyl, alfentanil, sufentanil). Alternatively, a new sponsor with sparse resources risks an extended development and running down the 20-yr patent clock.

Leveraging drug knowledge from other molecules in same class has some advantages, specifically in study design and the selection of endpoints. Remimazolam is pharmacodynamically similar to midazolam, while possessing a pharmacokinetic profile closer to that of propofol. PAION Pharma GmbH (Aachen, Germany), the developer of remimazolam, sensibly targeted procedural sedation as a lead indication with an eye on the lucrative U.S., Australian, and Scandinavian propofol sedation for colonoscopy business. After licensing based on comparisons with midazolam, there is plenty of time to cautiously explore nonanesthesiologist sedation with a fast-on, fast-off hypnotic. So far, so good. However, choosing development priorities beyond procedural sedation is not so straightforward. Further, the “me too” character of same-class developments limits the scope for exciting new applications, likely depresses pricing, and therefore profits.

The evanescent chemistry of remimazolam has consequences for extended administration. Specifically, repeated bolus dosing or continuous infusion uses a lot of drug. Consequently, even if the drug cost of limited procedural sedation is reasonably priced, maintenance of anesthesia is going to be expensive. PAION’s decision to target general anesthesia with a single format, i.e., “induction and maintenance,” presumably reflects the popularity of total intravenous anesthesia in some but not all European markets and the prospect of substantial product consumption during each case. However, undertaking a large phase 3 trial  comparing electroencephalogram-guided propofol or remimazolam anesthesia (in the shadow of COVID) proved time-consuming and undoubtedly delayed the licensure of that indication. This choice contrasted with the early development of propofol, that proceeded from bolus injections for induction to repeat bolus injections and infusions for short surgical cases with an eye on the trend toward day-stay surgery. Propofol total intravenous anesthesia for prolonged major surgery was not an initial priority. For anesthesiologists inexperienced with total intravenous anesthesia and perhaps lacking confidence to start using it, migration to remimazolam for anesthesia maintenance would be a huge step. Given that etomidate and even ketamine are still in use as induction agents, developing remimazolam for induction of anesthesia prior to maintenance with sevoflurane should be a priority and should probably have been prioritized over total intravenous anesthesia maintenance studies.

Helpfully, Asian investigators are showing us the way. Induction of anesthesia in hemodynamically unstable and other high-risk patients remains challenging. Midazolam is effective but shackled by unfavorable pharmacokinetics, remimazolam might offer some answers. Can it reliably provide a quality induction experience for patient and clinician? After maintenance of anesthesia with remimazolam, a minority of patients are slow to awaken.  Ad hoc use of flumazenil antagonism has been described in case reports and trials, but we need proper dose-finding studies and translation to clinical practice. Multiple investigators have compared flumazenil-reversed remimazolam sedation or anesthesia with propofol but failed to include a “no-flumazenil” group. We need three group studies, i.e., propofol, remimazolam, and remimazolam followed by flumazenil.

Children form a high proportion of surgical caseload but are often treated as an afterthought in drug development. Clinical dose estimation is often mistakenly scaled from adults. Adverse events and complications may be inappropriately assumed to be similar. Well-designed pediatric studies of anesthesia induction or “induction and maintenance” would be welcome. Current interests in the possibility of neonatal neurotoxicity from anesthesia add relevance and possibly challenges to pediatric anesthesia studies for new agents.

Pharmacokinetics is more than a dry academic subject, it underpins the way we use our drugs. With regard to remimazolam, there is more to do. Currently, remimazolam is dosed without regard to patient weight.  While this may be justifiable from a “purist” interpretation of data from early studies, it is counterintuitive in anesthesia where pretty much everything else is dosed on a per-kilogram basis. “Real-life” patients are highly heterogenous, certainly more so than those seen in trials. An extreme example is seen in volunteer studies, usually populated by young men who are phenotypically very similar. This is a poor basis for dose recommendations for patients weighing 40 to140 kg. Target controlled infusion is an established technique worldwide except in the United States. If remimazolam is to be used for maintenance of anesthesia, then a reliable target controlled infusion model is a must. This entails more than a parameter set describing a simple compartment model. We want to know parameter variance and covariates that account for that variance. The influence of fat mass, for example, is increasingly relevant as obesity becomes the new normal in some countries. Studies in children require an understanding of the influence of size and age, detailing maturation kinetics. Interactions between commonly used anesthesia drugs require quantification.

During clinical application of target controlled infusion, pharmacokinetic knowledge is used to determine a dose that will achieve a concentration predicted to produce a defined effect. It would be useful to understand the concentration–response relationships for remimazolam. For hypnosis, this could be detailed using the electroencephalogram or a clinical sedation score. Concentration–effect relationships are also relevant to adverse cardiovascular or respiratory effects. The effects of sedative drugs on a child’s airway are of major concern when the drug is used in remote locations such as the magnetic resonance imaging scanner and direct supervision is limited. Propofol’s pharmacodynamic interactions (beneficial and adverse) with opioids or other sedatives are well described. We await clarification of those interactions with remimazolam.

We do not need reports describing remimazolam sedation in yet another slightly different clinical scenario. Instead, investigators could explore the influence of the patient’s pathology or the surgery category or physiology on pharmacokinetics and pharmacodynamics. Consider the effect of raised intraabdominal pressure on fentanyl clearance⁴  or whether remimazolam’s effect is impacted by chronic benzodiazepine use. 

Presenting anesthetics in an injectable formulation is challenging and there is more to be done. Ester hydrolysis requires remimazolam be presented as a powder requiring dilution. This is annoying but manageable. After all, we cope with powdered remifentanil. However, the recommended dilution of remimazolam 20 mg to 2.5 mg/ml is bizarre. This gives 8 ml of solution and generates anomalies like a first dose for adult sedation of 2.8 ml. Really? What is wrong with 2 mg/ml or 1 mg/ml yielding 10 or 20 ml, respectively? This is particularly irksome for those working with children where dose errors are more common than adults. 

Anaphylaxis has been reported in patients receiving remimazolam. Given that it is currently formulated in dextran (a known allergen) this is probably not surprising. Immunologists can unpick whether these incidents were caused by remimazolam or dextran. However, some reports presented for publication do not even validate whether the reaction was truly anaphylaxis. In the meantime, company chemists could usefully be looking for a dextran-free formulation.

An early foray into remimazolam intensive care unit sedation foundered when some hard-to-explain pharmacokinetics were observed.  The heterogeneity of the intensive care unit population, concomitant drug use, routes of administration, and their sometimes-extreme degrees of physiologic derangement present safety challenges. Extended infusions into patients with hepatic or renal dysfunction risk accumulation of both parent drug and metabolites. Further, patients may be exposed to high metabolite concentrations requiring that the latter be truly inactive. Studies looking at intensive care sedation are difficult. Certainly, two intensive care studies of clonidine sedation for children have failed in the United Kingdom and Europe.  Review of those failures, a more nuanced pharmacokintic or pharmacodynamic population modeling approach, and conformity of care between units could produce better studies.

For a new drug to be successful it is not enough that it be novel, it also needs to be useful. Ciprofol produces less pain on injection than propofol. So what? Patients do not consider injection pain an important problem.  Further, it is easily prevented by pretreatment with lidocaine. Please can we see some head-to-head comparisons of injection pain with ciprofol compared to propofol plus lidocaine. If there is not any difference then all we are left with is ciprofol’s higher potency, and this does not pass the “so what” test. Who cares? We do not remember years of people complaining that propofol is insufficiently potent.

Journals and their readers would all like news of “game changers,” new drugs that truly make a difference. Mostly we have been offered solutions to problems of no real importance or “improvements” that simply do not work. Thus, nobody needs a closed-loop system to administer rocuronium epidural morphine foam never gained traction, a propofol prodrug is a bad idea, and liposome bupivacaine is (controversially) probably no better than plain. 

These projects would have benefited from some critical thinking at the concept stage. If you were investing your savings, you would want to know: what is the unmet medical need? What is the economic case for the drug? What is the cost of development? New drugs are expensive. Nobody is going to pay for a drug that does something trivial, like reduce pain on injection. To justify the extraordinary cost of drug development, it is important to really be a game changer. For example, if people could drive home after procedural sedation with remimazolam, that would be a game changer. Waking up a few minutes faster: not so much. What about ciprofol would be a game changer? We are not aware of anything.

Innovations in other specialties may affect our practice. Glucagon-like peptide 1 (GLP-1) agonists appear to benefit both type 2 diabetes and generic obesity but may delay gastric emptying and potentially increase the risk of aspiration of gastric contents.  In anesthesia we have our own problems to solve and horizons to march toward. Could we have a hypnotic like ketamine without psychosis? A sedative-analgesic for colonoscopy that is compatible with driving home (the Europeans have one, it is called nitrous oxide…).  Nonopioid oral analgesia without non-steroidal anti-inflammatory drug side effects. We certainly have meaningful targets. Equally, real innovation is possible. Recently, a capsaicin prodrug, vocacapsaicin has shown long-lasting postoperative analgesia after bunionectomy (a painful outpatient procedure). This appears to be a significant step on the anti-opioid journey, as does oliceridine—an opioid with decreased respiratory depression.

In conclusion, thorough investigation of new drugs is helpful and informative. However, before committing to yet another ciprofol or remimazolam study, potential investigators will be well advised to consider whether they are asking the right question—and if not, desist. Game changers are unpredictable but, like the late-night bus, you will know one when you see it…