Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects

Valk, Beatrijs I.; Absalom, Anthony; Meyer, Peter; Meier, Sascha; Daas, Izaak den; Amsterdam, Kai van; Campagna, Jason; Sweeney, Steven; Struys, Michel

doi:10.1016/j.bja.2018.01.038

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…5 Notable side effects of ABP-700 include the occurrence of excitatory phenomena such as involuntary muscle movements, tachycardia, and tachypnea. 5,8 Although recent preclinical studies showed that CPM-acid can inhibit the GABA A receptor, a potential mechanism for seizure induction, 9 this effect was only seen at concentrations two orders of magnitude greater than those achieved clinically.…”

Section: Discussionmentioning

confidence: 99%

“…As we developed the BIS model, we found that the initial model did not have a satisfactory fit. Based on our observation that increased BIS values were reported in subjects experiencing severe involuntary muscle movements, 5,8 we then decided to separate the BIS effect into a suppression Recirculation Model of ABP-700…”

Section: Discussionmentioning

confidence: 99%

“…This analysis involves data from five studies of the safety and tolerability of ABP-700 (see Supplemental Digital Content 1, http://links.lww.com/ALN/C493): ANVN-01 5 (bolusonly dose escalation study), ANVN-02 8 (infusion dose escalation study), ANVN-03 (bolus-only dose optimization study, venous samples only), ANVN-04 (infusion dose optimization study), and ANVN-05 (induction dose study). In various cohorts, pretreatment in the form of an opioid agent or benzodiazepine was administered before administration of ABP-700.…”

Section: Study Executionmentioning

confidence: 99%

“…ABP-700 were assessed as described by Struys et al 5 and Valk et al, 8 by assessment of adverse events, safety laboratory tests, intermittent 12-lead electrocardiograms, temperature, and infusion site reaction monitoring. Continuous monitoring of three-lead electrocardiogram, heart rate, pulse oximetry, noninvasive blood pressure (every minute), continuous arterial blood pressure, respiration rate and pattern, and end-tidal carbon dioxide were monitored in all subjects using a Philips MP50 monitor (Philips, The Netherlands).…”

Section: Study Executionmentioning

confidence: 99%

“…Instead, the responsible clinicians recorded their observations on the character and extent of the involuntary muscle movements electronically. Involuntary muscle movement severity was evaluated by post hoc analysis of the recorded observations as described by Struys et al 5 and Valk et al 8 Involuntary muscle movements were defined as "extensive" when they involved the whole body or a considerable part of it. Involuntary muscle movements were defined as "few movements" when they were observed in a few body parts, such as in both arms or both legs.…”

Section: Study Executionmentioning

confidence: 99%

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Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700

et al. 2020

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Background γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scores. Methods Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. Results The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. Conclusions The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Study Executionmentioning

confidence: 99%

Section: Study Executionmentioning

confidence: 99%

Section: Study Executionmentioning

confidence: 99%

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Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700

et al. 2020

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Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients

et al. 2022

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Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics

Valk

Struys

2021

Clin Pharmacokinet

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Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.

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Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects

Abstract: NTR4735.

Cited by 23 publications

References 35 publications

Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700

Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients

Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics

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