Gantacurium chloride


Gantacurium chloride is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.
Gantacurium is no longer in clinical development.

History

Gantacurium represents the third generation of tetrahydroisoquinolinium neuromuscular blocking drugs in a long lineage of compounds invented by medicinal chemists and scientists at Burroughs Wellcome Co., Research Triangle Park, North Carolina. Unlike all other clinically used tetrahydroisoquinolinium agents except cisatracurium, gantacurium is a stereo- and regioselective single isomer. And unlike any other traditional symmetrical predecessors in the family of bisbenzyltetrahydroisoquinolinium neuromuscular-blocking drugs, gantacurium is an asymmetric ''bis-onium ester of α-chlorofumaric acid: this particular feature arises solely from the -trans benzyltetrahydroisoquinolinium moiety at one onium head and a -trans phenyltetrahydroisoquinolinium moiety at the other onium head. The chlorine atom lies on the same side of the double bond as the benzyl-THIQ moiety. Although the carboxylic acid groups are in opposite relationship across the double bond, as in fumaric acid , the chlorine atom is given the higher priority, so it's named as a -configuration at this stereobond.
The lineage of compounds leading to the rational discovery of gantacurium stems from seminal research in tetrafluorosuccinic acid-derived bisbenzyltetrahydroisoquinolinium esters first synthesized in February 1991 by a postdoctoral Fellow and James C. Wisowaty, PhD, in the Chemical Development Laboratories at Burroughs Wellcome Co. in collaboration with John J. Savarese, MD. The synthesis of symmetrical halofumarate and halosuccinate esters was prompted by initial attempts to make bis-onium tetrafluorosuccinic acid esters —the novel idea of a tetrafluorosuccinate linker between two onium heads being prompted by Roy A Swaringen, PhD. It was very quickly realized, however, that the tetrafluorosuccinic acid esters were too unstable for isolation in sufficient quantities for extensive in vitro or in vivo preclinical evaluations. To circumvent the in situ instability of the fluoro derivatives, synthesis of bis-onium dichloro- and dibromosuccinates was undertaken: that in itself lead to complex intractable mixtures of mono- and di-halofumarate and halosuccinate compounds. The mixtures were inseparable initially but proved to be promising: in vivo tests of these mixtures in a cat model pointed to potential leads for a compound with the highly prized duality of a rapid onset of action and an ultrashort duration of action. This led to the synthesis of prototypical bisbenzyltetrahydroisoquinolinium halofumarate esters in April 1992: compounds 1710W92 and 1975W92, both of which were noted for their ultrashort durations of action, and would differ structurally only very slightly from the future gantacurium in their stereochemistry and symmetry. Indeed, the idea of exploring asymmetric tetrahydroisoquinolinium esters had already been seeded with parallel and earlier syntheses of another series of asymmetric potential neuromuscular blocking agents, although the original concept for asymmetricity in the design of new neuromuscular blocking drugs dates back to 1962 with reported combinations of the respective halves of laudexium and succinylcholine modeled, presumably, on the asymmetric structure of the prototypical neuromuscular blocking agent d''-tubocurarine that made its entry into anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital.
Very shortly after the breakthrough in May 1992, however, Patel relinquished his Fellowship and further progress languished until late 1993/early 1994 when the research was resumed by another team of Burroughs Wellcome Co. chemists led by Eric Bigham PhD and Evan Boswell PhD: a series of stereoselective halofumarate and halosuccinate compounds were synthesized and tested for further lead optimisation. Again, however, the untimely intervening merger between Burroughs Wellcome Co. and its rival Glaxo Inc. to form the now non-existent GlaxoWellcome Inc. during 1995 resulted in even further delays to progress in optimizing the halosuccinate and halofumarate series of neuromuscular blocking drugs.
It was not until late in 1995 that further research and lead optimization was re-initiated by yet another team of medicinal chemists at GlaxoWellcome Inc. this time led by Eric E. Boros PhD, Robert A. Mook Jr. PhD, and Vicente Samano PhD. The team's work rapidly led to the first synthesis of GW280430A in 1996. Patents for gantacurium were subsequently applied for and issued in 1998.

Neuromuscular function parameters: definitions

The clinical arena of neuromuscular blocking agents is a minefield of jargonistic language, and some definitions below help to clarify:
  • Train-of-Four response: stimulated muscle twitch response elicited in trains of four when stimuli are applied in a burst of four stimuli versus single stimuli
  • ED95 dose: the dose of any given neuromuscular blocking agent required to produce 95% suppression of muscle twitch response under balanced anesthesia
  • T25% : the calculated difference in time between time of injection of drug and time to 25% recovery from neuromuscular block—this parameter defines the clinically effective neuromuscular block
  • T75% recovery: the calculated difference in time between time of injection of drug and time to 75% recovery from neuromuscular block
  • T95% recovery: the calculated difference in time between time of injection of drug and time to 95% recovery from neuromuscular block—this parameter effectively defines the timepoint at which full recovery from neuromuscular block is observed
  • 25%–75% recovery index: the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value—this parameter is an indicator of the rate of recovery from neuromuscular block
  • 5%–95% recovery index: the difference in time between the time to recovery to 5% and time to recovery to 95% of baseline value—another parameter that is an indicator of the rate of recovery from relatively complete block to full recovery from neuromuscular block
  • T4:T1 ≥ 0.7: a 70% ratio of the fourth twitch to the first twitch in a TOF—provides another measure of the recovery of neuromuscular function
  • T4:T1 ≥ 0.9: a 90% ratio of the fourth twitch to the first twitch in a TOF—provides another measure of the full recovery of neuromuscular function

    Pharmacological action: definitions

In anesthetic clinical practice, neuromuscular blocking agents tend to be distinguished from each other based on their onset and duration of pharmacological action. The adjectives defining both the onset and duration were previously used arbitrarily and generally motivated by competition between the pharmaceutical companies marketing these agents. The arbitrary approach to the adjectives describing onset and duration was finally settled with definitive advice "from the FDA" in January 1995:
AdjectiveUltra-rapid / Ultra-shortRapid / ShortIntermediateSlow / Long
Clinical Onset
<11–22–4>4
Clinical Duration
<88–2020–50>50
Recovery Time
<1525–3050–7090–180
Recovery Index 2–3610–15>30

Preclinical pharmacology

The preclinical pharmacology development of GW280430A has been studied in the cat, dog, and monkey models that have been the backbone of successful predecessor bistetrahydroisoquinolinium neuromuscular blocking drugs development projects such as atracurium, doxacurium, mivacurium and cisatracurium, and others that were evaluated but not approved for clinical utility, e.g., BW A444.

Clinical pharmacology and pharmacokinetics

The first clinical trial of GW280430A was conducted in a small cohort of healthy US volunteers in December 1997 at the New York Presbyterian-Weill Cornell Medical Center, New York City. The study confirmed that, with propofol/fentanyl/N2O/O2 anesthesia, gantacurium has a rapid onset of action and an ultra-short duration of action. Additionally, the spontaneous recovery rate was rapid, predictable, and independent of dose administered, indicating a lack of cumulative neuromuscular blocking effect: the 25–75% recovery index was 3 minutes, and complete recovery to TOF of 90% occurred ≤15 minutes. These data are secured from a small sample size, tempering any broad conclusions to be drawn until clinical studies with larger sample sizes are conducted.
In early 1998, shortly after conducting the first clinical study, GlaxoWellcome Inc. undertook a strategic decision to outlicense its US anesthesia research portfolio and franchise. Further clinical development of GW280430A therefore ceased until the portfolio was licensed in May 2002 to a now-defunct start-up company called Avera Pharmaceuticals. Meanwhile, in the intervening period, scientists at the former GlaxoWellcome Inc. had conducted further research and developed a proprietary buffer excipient formulation intended to mitigate the mast cell degranulation seen upon rapid intravenous administration of high concentration doses of agents such as GW280430A that are intrinsically cationic. In 2003, a newly reformulated version of GW280430A, using the licensed buffer excipient from GlaxoSmithKline, was re-investigated in a second clinical study in healthy US volunteers to compare the improvement in safety margin versus that with the original formulation. Success with the reformulated gantancurium in healthy volunteers led to initiation and conduct of a randomized, controlled, phase II multicenter European study investigating its utility for endotracheal intubation in 230 patients undergoing surgical anesthesia. The phase II study was completed successfully by Spring 2006: >90% of patients administered with gantacurium were assessed to have acceptable tracheal intubation within 60 seconds of its injection. However, a peer-reviewed full publication of these data from this European study has yet to be published, despite early presentation of these data as abstracts.
Gantacurium is currently under phase III clinical development by Maruishi Pharmaceutical Co. Ltd., which licensed the compound from Avera Pharmaceuticals. Maruishi is better known in the world of anesthesia for its invention of sevoflurane, a commonly used gaseous anesthetic agent.
The singular distinguishing clinical feature of gantacurium from any other non-depolarizing neuromuscular blocking drug clinically tested is that it has the desired duality of a rapid onset and an ultrashort duration of action even when administered at 3–4 times the ED95 doses. With the exception of one other clinically tested agent, BW785U77, no other clinically administered neuromuscular blocking drug has matched this feat to date: all other non-depolarizing neuromuscular blocking drugs clinically administered at equivalent doses most certainly would result in a medium or long duration of action albeit with a rapid onset of paralyzing effect. In this sense, gantacurium is a first in its class non-depolarizing neuromuscular blocking drug to arguably challenge the pharmacological profile of the gold-standard ultrashort acting depolarizing agent succinylcholine. BW785U77 was not pursued for further clinical development owing to its propensity for eliciting histamine release in humans with more intensity than that observed during pre-clinical evaluation in animals. The holy grail of research in the neuromuscular blocking drugs arena for the better part of the 1980s and 1990s has been to find a non-depolarizing replacement for succinylcholine.
Preliminary in vitro investigations indicate that the in vivo pharmacological activity likely undergoes rapid "chemo-inactivation" via cysteine adduct formation followed by slow biodegradation via ester hydrolysis. The pharmacologically inert cysteine adduct subsequently undergoes ester hydrolysis and the by-products are eliminated via renal and/or hepatic mechanisms. Unlike the pH- and temperature-dependent chemodegradation seen with atracurium and cisatracurium, the inactivation of gantacurium via cysteine adduct formation is independent of body pH and temperature.
The use of extrinsically administered cysteine to deliberately accelerate reversal of the pharmacological effect of fumarate bis-onium neuromuscular blocking drugs is being investigated currently.