Key result
Omadacycline attenuated parasympathetic influence on heart rate via M2 receptor binding but had no effect on hERG channel activity or QTc in monkeys at doses up to 40 mg/kg.
Why the study?
Does omadacycline have the potential to induce cardiac arrhythmia or cardiovascular toxicity in preclinical models?
Does omadacycline have the potential to induce cardiac arrhythmia or cardiovascular toxicity in preclinical models?
Omadacycline demonstrates a low potential for inducing cardiac arrhythmias or significant cardiovascular toxicity in preclinical models, despite binding to M2 receptors.
Answers are grounded in this paper and cite their sources.
Preclinical data suggest low omadacycline cardiotoxicity; hypothesis-generating and should not yet change practice.
Omadacycline is a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacterial pathogens. A series of nonclinical studies, including mammalian pharmacologic receptor binding studies, human ether-a-go-go-related gene (hERG) channel binding studies, studies of the effects on ex vivo sinoatrial (SA) node activity, and studies of in vivo effects on cardiovascular function in the cynomolgus monkey, was undertaken to assess the cardiovascular risk potential. Omadacycline was found to bind almost exclusively to the muscarinic subtype 2 acetylcholine receptor (M2), and in the SA node model it antagonized the effect of a pan-muscarinic agonist (carbamylcholine) in a concentration-dependent manner. Omadacycline exhibited no effect on hERG channel activity at 100 μg/ml (179.5 μM), with a 25% inhibitory concentration of 166 μg/ml (298.0 μM). Omadacycline had no effect on QTc in conscious monkeys at doses up to 40 mg/kg of body weight. Overall, omadacycline appears to attenuate the parasympathetic influence on the heart rate but has a low potential to induce cardiac arrhythmia or to have clinically significant cardiovascular toxicity.
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Tanaka et al. (2016) studied this question. Omadacycline was evaluated on Cardiovascular risk potential (hERG channel activity, QTc, M2 receptor binding). Omadacycline attenuated parasympathetic influence on heart rate via M2 receptor binding but had no effect on hERG channel activity or QTc in monkeys at doses up to 40 mg/kg.
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