When it comes to innovative anesthetic sedative drugs launched in recent years, remimazolam is undoubtedly a variety worthy of attention.

Remimazolam was designed and synthesized by GSK in 1999. After changing hands many times, it was approved for marketing in China, the United States, Europe and other countries almost simultaneously around 2020.

However, the author found that the sales volume of the drug after its launch in different countries varies greatly. In 2023, the sales volume of remimazolam in China was about 40 million US dollars, while that in the United States was only 800,000 US dollars, which is about 2% of the Chinese market. Why is there such a difference? It is reported that remimazolam,

a "new star" in the field of anesthesia, is an ultra-short-acting GABAA receptor agonist that combines the characteristics of midazolam and remifentanil, two anesthetics. Like midazolam, it acts on GABA receptors, but like remifentanil, it does not rely on organ metabolism. It can be quickly metabolized by carboxylesterase in the liver to produce inactive metabolites in the body, so that its sedative effect disappears quickly and the sedation recovery time is short.

The design and discovery of this drug can be traced back to 1999. Inspired by remifentanil, GSK successfully designed and synthesized remimazolam and submitted a patent application. However, not long after, GSK transferred the patent to the British company TheraSci. After several corporate mergers and reorganizations, Paion began to develop this drug in 2008.

In early related studies, due to the instability of the free base of remimazolam, the free molecules of remimazolam could only be stored at a low temperature of 5°C, and salt formation was required to improve its physical and chemical properties. Paion developed remimazolam besylate, and Hengrui Medicine used a slightly different (toluenesulfonic acid) salt form of remimazolam. At present, both salt forms of remimazolam have been approved for marketing, of which remimazolam tosylate has only been approved for marketing in China; while remimazolam besylate has been approved for marketing in China, Japan, the United States, Europe and other countries, but the indications are quite different.

In the Chinese market , in 2012, Renmin Pharmaceutical successfully acquired the Chinese market rights of remimazolam besylate with a down payment of 3 million euros. In July 2020, the National Medical Products Administration approved the use of remimazolam besylate for injection for "sedation for colonoscopy", and added two new indications of "induction and maintenance of general anesthesia" and "sedation for bronchoscopic diagnosis and treatment" in March and July 2022, respectively.

In the US market , in July 2020, remimazolam besylate was approved for marketing under the trade name Byfavo, with the indication of procedural sedation within 30 minutes. It is currently sold by Eagle.

In Japan and South Korea , remimazolam besylate is approved for induction and maintenance of general anesthesia.

It is worth mentioning that in the first quarter of 2024, Paion was acquired by Renmin Pharmaceutical, which means that the global rights of remimazolam besylate have been owned by Renmin Pharmaceutical.

Remimazolam tosylate was first approved for marketing in China in 2019, with indications including induction and maintenance of general anesthesia and sedation during colonoscopy.

Behind the difference in sales volume between

China and the United States Although remimazolam was approved for marketing in China and the United States at almost the same time, there were significant differences in commercial performance, which attracted the attention and discussion of industry insiders.

On the one hand, some experts believe that the range of indications approved for remimazolam in different countries is different, resulting in large differences in its sales in various countries.

In the United States, remimazolam has only been approved for procedural sedation, with sales of only about $800,000 in 2023. In China, remimazolam has been approved for multiple indications such as general anesthesia and sedation, with sales of about $40 million in 2023, accounting for most of the global sales. Similarly, in Japan and South Korea, remimazolam has also been approved for general anesthesia indications, with a total sales of about $8 million in the two places, far exceeding the US market. It can be seen that remimazolam has a larger sales market in the field of general anesthesia than in the field of sedation.

On the other hand, some experts believe that the sales performance of remimazolam in the Chinese and American markets is very different, and there may be concerns about its metabolites behind this.

She pointed out, "After remimazolam is infused into the body, it is hydrolyzed by esterase in the liver into its carboxylic acid metabolite (CNS7054) and methanol; methanol may be oxidized into formaldehyde and formic acid in the body. Formaldehyde has active chemical properties and is easy to react with molecules such as DNA and proteins, causing DNA conformational changes, cell damage and tissue toxicity, which poses a safety hazard. Studies have shown that when crab-eating monkeys or rhesus monkeys absorb a large amount of methanol, only methanol and a small amount of formic acid can be detected in the body, and it is difficult to detect formaldehyde."

"In addition, formic acid in the metabolites of remimazolam may also inhibit the activity of carboxylesterase, thereby affecting the metabolic decomposition of remimazolam in the body. In the Phase II clinical trial, Japan's Ono company found that some subjects had unexplained high blood drug concentrations of remimazolam, which led to its withdrawal from the development of remimazolam. This may be related to the effect of the above-mentioned metabolites on carboxylesterase activity. To date, the FDA has stipulated that remimazolam can only be infused within 0.5 hours. This may be based on a high degree of vigilance against the potential hazards of the accumulation of drug metabolites, aiming to ensure that its use does not lead to the accumulation of methanol and its metabolites (formaldehyde, formic acid) to dangerous levels, thereby avoiding toxic effects on patients."

She also added: "A small amount of methanol may also be generated during the fermentation process of red wine production. Therefore, the country has clear regulations on the methanol content of wine. The methanol content in red wine must be less than or equal to 400 mg/L, and the methanol content in white wine and rosé wine must be less than 400 mg/L. Or equal to 250mg/L. However, the wine sales group is healthy people, and the human body can process and metabolize the toxicity of small amounts of methanol and formaldehyde through some physiological mechanisms. Therefore, the small amount of methanol contained in wine usually does not cause harm to healthy people.

But remimazolam is aimed at frail patients, whose physiological functions are reduced and who are more sensitive to the dangers of methanol and formaldehyde. In order to avoid possible surgical risks, the content of methanol in injectable drugs is strictly controlled. The ICH (International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) Guidelines for Residual Solvents in Drugs (ICH-Q3C) stipulates that the limit of methanol should be controlled within 3000PPM. "

At present, the commonly used anesthetic sedatives in clinical practice include propofol, benzodiazepines (represented by midazolam), α receptor agonists (represented by dexmedetomidine), etc., all of which have their own shortcomings: midazolam metabolites are still active and significantly prolong the patient's awakening time; propofol has a greater impact on the circulatory and respiratory systems.

Although there is still room for improvement in some aspects of remimazolam, its unique advantages cannot be ignored, such as rapid onset of action, rapid metabolism, and rapid recovery from sedation. With the advancement of medical technology and in-depth exploration of clinical applications, there may be an "improved version of remimazolam" on the market in the future, bringing new options to the field of anesthesia and sedation.

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