move top
컨텐츠 바로가기

Byfavo
A Novel Ultra-Short Acting Anesthetic/Sedative Under Development at Hana Pharm

HOME Research & Development Byfavo Inj.

Byfavo.

A Novel Ultra-Short Acting Intravenous GABA Alpha Receptor Modulator

Anesthetic/sedative of the future

Similar to its analgesic sibling remifentanil, Byfavo represents another member of the soft drug class, featuring favorable pharmacokinetic profile.

It provides a softer, faster & cleaner general anesthetic/sedative for anesthesiologists & patients undergoing general anesthesia, procedural sedation, and ICU sedation beyond 24 hours.

I. Soft Byfavo

 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. They are therapeutic agents that undergo predictable metabolism to convert into inactive metabolites after exerting their therapeutic effect. They are designed 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]

Byfavo was developed with this soft drug design in mind, modifying a known drug to create an analogue with improved pharmacokinetic properties

The development process of Byfavo Inj. included adding a metabolically labile ester moiety to a structure derived from the benzodiazepine class. This modification allowed Byfavo to be Inj.highly susceptible to hydrolysis by tissue esterases.7] The methyl ester undergoes dose-independent ester hydrolysis and converts Byfavo into its inactive metabolite, CNS 7054. 2]

II. Fast Byfavo

 Aspects of soft drugs designs that are particularly interesting to anesthesiologists include rapid onset of effect and quick recovery. 3]
Byfavo is an ultra-short acting anesthetic agent/sedative that is 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 Byfavo is approximately three times faster than the clearance of midazolam. 2] Byfavo has a rapid CSHT (Context-Sensitive Half-Time) of 7 min, for a continuous IV infusion of up to 4 hours. 10] The CSHT profile for Byfavo is similar to remifentanil even for infusions up to 8 hours.

III. Clean Byfavo

 Byfavo shows high extrahepatic clearance, and since its metabolism does not rely on cytochrome enzymes, metabolic interactions with other drugs in the liver is limited. 7] A Phase I trial confirmed its safety even in Japanese patients with mild to moderate hepatic disorders. 11] Also in general anesthesia, no dose adjustment was necessary even in patients with end-stage renal disease. 11]
Availability of a specific antagonist (flumazenil, Lumasate Inj, Hana Pharm) further verifies Byfavos’ cleanness and safety, in case of overdose. It offers a broad therapeutic window for induction and maintenance of general anesthesia, with no residual effects observed after awakening. Its neutralization by an enzyme present in extrahepatic tissues decreases the likelihood of drug accumulation, and thus decrease occurrence of syndromes like "propofol infusion syndrome". 2,9]

Unparalleled Novelty of Byfavo "Independency"

 1. Organ-independent elimination: Byfavo can be administered safely in patients with hepatic or renal impairment. 2,11]
2. Dose-independent ester hydrolysis: Byfavo is converted into its inactive metabolite, CNS7054, rapidly. 2]
3. Body-weight-independent systemic clearance (model-independent clearance). 5] 
4. 4. Infusion duration (up to 4 hours) 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. (2000). Soft drug design: general principles and recent applications. Medicinal research reviews, 20(1), 58–101. https://doi.org/10.1002/(sici)1098-1128(200001)20:1<58::aid-med3>3.0.co;2-x
2] Bansal, S., Singhal, S. (2018) Remimazolam (CNS7056): an Emerging Sedative and General Anaesthetic. Journal of Clinical and Diagnostic Research, 12(3), UE01-03. https:doi.org/10.7860/jcdr/2018/30823.11263
3] Johnson K. B. (2012). New horizons in sedative hypnotic drug development: fast, clean and soft. Anesthesia and analgesia, 115(2), 220-222. https:doi.org/10.1213/ANE.0b013e31825ef8d7
4] New anesthesia drugs developed to be 'fast, clean and soft'. (2012). Retrieved 26 April 2021, from https://www.sciencedaily.com/releases/2012/07/120731123251.htm
5] Antonik, L. J., Goldwater, D. R., Kilpatrick, G. J., Tilbrook, G. S., & Borkett, K. M. (2012). 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. Anesthesia and analgesia, 115(2), 274–283. https://doi.org/10.1213/ANE.0b013e31823f0c28
6] Wiltshire, H. R., Kilpatrick, G. J., Tilbrook, G. S., & Borkett, K. M. (2012). A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesthesia and analgesia, 115(2), 284–296. https://doi.org/10.1213/ANE.0b013e318241f68a
7] Preclinical studies conducted by ONO Pharmaceuticals; publication in preparation
8] Di L. (2019). The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics. Current drug metabolism, 20(2), 91–102. https://doi.org/10.2174/1389200219666180821094502
9] Hemphill, S., McMenamin, L., Bellamy, M. C., & Hopkins, P. M. (2019). Propofol infusion syndrome: a structured literature review and analysis of published case reports. British journal of anaesthesia, 122(4), 448–459. https://doi.org/10.1016/j.bja.2018.12.025
10] Schüttler, J., Eisenried, A., Lerch, M., Fechner, J., Jeleazcov, C., & Ihmsen, H. (2020). Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers. Anesthesiology, 132(4), 636-651. doi: 10.1097/aln.0000000000003103
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


Source : 7]