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REMIMAZOLAM
A novel ultra-short acting anesthetic/sedative under development at Hana Pharm

HOME Research & Development Remimazolam

REMIMAZOLAM [HNP-2001]

A novel ultra-short acting intravenous GABA alpha receptor modulator

Anesthetic/sedative of the future

Similar to its analgesic sibling remifentanil, remimazolam represents another member of the soft drug class, featuring a favourable pharmacokinetic profile

Softer, Faster & Cleaner General Anesthetic/Sedative for Anesthesiologists & Patients undergoing General Anesthesia, Procedural Sedation and ICU Sedation beyond 24hours 

I. Soft Remimazolam

Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. They are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified 1]

Remimazolam is developed by rational drug design , modifying a known drug to create an analogue with improved pharmacokinetic properties.

Remimazolam has been developed by adding a metabolically labile ester moiety to a structure derived from the benzodiazepine class. This modification makes remimazolam highly susceptible to hydrolysis by tissue esterases 7]
Remimazolam is a methyl ester which undergoes dose independent ester hydrolysis and is converted into its inactive metabolite, CNS 7054. 2]

II. Fast Remimazolam

Aspects of soft that are of particular interest to anesthesiologists include rapid onset of effect and quick recovery 3]
Remimazolam is an ultra-short acting anesthetic agent/sedative and rapidly metabolized to an inactive metabolite by CES1, one of the predominant drug metabolizing enzymes of liver and other organs, e.g. kidney, brain, lung 7,8] Its clever design results in fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than older sedatives of the benzodiazepine class currently available on the market.4]

The plasma clearance of remimazolam is approximately three times more rapid than the clearance of midazolam.2] Remimazolam has a rapid CSHT (Context-Sensitive Half-Time) of 7 min, for a continuous i.v. infusion of up to 4 h.10] The CSHT profile for remimazolam is similar to remifentanil even for infusions up to 8 hours.

III. Clean Remimazolam

Remimazolam shows high extra hepatic clearance, and since its metabolism does not rely on cytochrome enzymes, it confers little scope for metabolic interactions with other drugs in the liver7] A Phase I trial confirmed its safety even in mild to moderately hepatically impaired Japanese patients.11] In general anaesthesia, no dose adjustment was necessary even in patients with end-stage-renal-disease.11]
Availability of a specific antagonist (flumazenil, Lumasate Inj, Hana Pharm) adds to its cleanness and safety in case of overdose. It offers a broad therapeutic window for induction and maintenance of general anaesthesia, with no residual effects observed after wake-up. Its inactivation by an enzyme also present in extrahepatic tissues decreases the chances of drug accumulation , and thus the chances of development of syndrome like "propofol infusion syndrome" are also rare.2,9]

Unparalleled Novelty of remimazolam  "Independency"

1. Organ independent-elimination: remimazolam can be safely used in patients with hepatic or renal impairment 2,11]
2. Dose independent –ester hydrolysis and conversion into the inactive metabolite, CNS70542]
3. Body Weight independent- systemic clearance (model-independent clearance) 5] 
4. Infusion duration (up to 4hours) independent - rapid CSHT (7 minutes)3]6]10]
5. Metabolic inactivation mediated by carboxylesterase 1 and independent of liver cytochrome system. 7]


References
1] Bodor N, Buchwald P. Soft drug design: general principles and recent applications, Med Res Rev 2000;20:58-101
2] Sumit Bansal, Shunah Singhal Remimazolam(CNS7056):an Emerging Sedative and General Anaesthetic, Journal of Clinical and Diagnostic Research,2018 Mar, Vol-12(3):UE01-UE03
3] Ken B.Johnson, New Horizons in Sedative Hypnotic Drug Development: Fast, Clean and Soft, International Anesthesia Research Society,2012:Volume 115 Nr.2
4] International Aesthesia Research Society(IARS)." New ansthesia drugs developed to be 'fast, clean and soft'. ScienceDaily,31 July 2012
5] Laurie J Antonik,D Ronald Goldwater,Gavin Kilpatrick, Gary S Tilbrook. A placebo and midazolam-controlled phase I single ascending dose study evaluating the safty, pharmakokinetics and phamacodynamics of remimazolam(CNS7056): Part I. Safety, Efficacy, and Basic Pharmakokinetics Anesthesia and analgesia 2011;115(2):274-83
6] Wiltshire HR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo and midazolam-controlled phase I single ascending dose study evaluating the safty, pharmakokinetics and phamacodynamics of remimazolam(CNS7056): Part II. Population pharmacokinetic and pharmacodynamic modelling and simulation Anesth.Analg. 2012;114:284-96 
7] Preclinical studies conducted by ONO Pharmaceuticals; publication in preparation
8] Di L., Current Drug Metabolism, 2019, 20, 91-102
9] Hemphill et al, Propofol infusion syndrome: a structured literature review and analysis of published case reports, British Journal of Anaesthesia, 122 (4): 448e459 (2019)
10] Schüttler et al., Anaesthesiology 2020.
11] Unpublished clinical trial results ONO Pharmaceuticals & PAION, publication in preparation.
7] Douglas K. Rex, MDCorrespondence information about the author MD Douglas K. Rex, Raj Bhandari, MD, Taddese Desta, MD, Michael P. DeMicco, MD, Cynthia Schaeffer, MD, Kyle Etzkorn, MD, Charles F. Barish, MD, Ronald Pruitt, MD, Brooks D. Cash, MD, Daniel Quirk, MD, Felix Tiongco, MD, Shelby Sullivan, MD, David Bernstein, MD A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy the American Society for Gastrointestinal Endoscopy Volume 88, Issue 3, Pages 427–437


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