In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline.
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.
Paratek Pharmaceuticals, Boston, Massachusetts, USA.
S Ken
SK
Tanaka
Paratek Pharmaceuticals, Boston, Massachusetts, USA stephen.villano@paratekpharma.com.
Stephen
S
Villano
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome; D008252:Macaca fascicularis; D008297:Male; D009924:Organ Culture Techniques; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects*; D013754:Tetracyclines / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D020746:Calcium Channels, L-Type; D018679:Cholinergic Agonists; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D043783:Receptor, Bradykinin B1; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D017470:Receptors, Glutamate; D011968:Receptors, Histamine; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D013754:Tetracyclines; C000591640:omadacycline; D002217:Carbachol