{"id":2676,"date":"2016-09-13T05:48:25","date_gmt":"2016-09-13T09:48:25","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2676"},"modified":"2016-09-20T12:28:02","modified_gmt":"2016-09-20T16:28:02","slug":"timely-new-information-on-next-generation-tetracyclines-part-1-omadacycline-and-cardiac-aes","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/09\/13\/2676\/timely-new-information-on-next-generation-tetracyclines-part-1-omadacycline-and-cardiac-aes\/","title":{"rendered":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 1: Omadacycline and Cardiac AEs"},"content":{"rendered":"

\"Horserace<\/a><\/p>\n

Several\u00a0interesting articles appeared recently which shed light on the efficacy of eravacycline and the safety of\u00a0omadacycline, both in Phase 3 and both in a head-to-head race to the market.\u00a0 Well, the term \u2018race\u2019 is bit of a stretch as both drugs have seen very significant delays in development. Omadacycline from Paratek has lost many years due to program changes, corporate reshuffling and changing partnerships to the point that its remaining patent life is now rather short. Eravacycline from Tetraphase has suffered a serious setback last year; the company had to restructure its\u00a0pivotal trial program and adjust submission timelines.\u00a0

Please refer to our earlier blogs on both compounds for details and insights <\/span><\/p>\n<\/div><\/p>\n

Today in Part 1 we review a paper by Tanaka et al. which deals with the effect of omadacycline on the heart [1]<\/a>. Preclinical investigations showed that omadacycline is a blocker of muscarinic M2 receptors in the heart, blocking vagal parasympathomimetic imput in a dose-dependent fashion. This affects several cardiac tissues, but especially the sinus (SA) node. Not surprisingly, tachycardia and an increase in blood pressure were\u00a0seen\u00a0in cynomolgous monkeys exposed to omadacycline. In fact, the magnitude of the effect was quite pronounced if not alarming: pulse rate increases between 27 to 58 bpm, and systolic blood pressure rises\u00a0of 5 to 23 mmHg over controls were observed.<\/p>\n

Well, nobody likes to administer\u00a0a drug that whips the heart into overdrive during an infection. Fortunately, this is unlikely to happen in real life. Tanaka et al.\u00a0refer us to clinical\u00a0data from Phase 1 and 2 studies suggesting\u00a0that cardiac M2 effects were rather modest, if not\u00a0irrelevant. However, the reference provided – an article by Noel\u00a0[2]<\/a>\u00a0 – only mentions effects on heart rate, not on blood pressure. It almost seems as if this Phase 2 cSSSI trial was\u00a0conducted\u00a0before<\/u> the full M2 effects of the drug became\u00a0known. It is also unclear whether rigorous cardiac monitoring was conducted in this study beyond capturing\u00a0standard vital signs. In any event, the AE profile of omadacycline in this Phase 2 study was tigecycline-like (mainly GI effects with nausea\/vomiting); there was\u00a0no\u00a0mention of cardiac or vascular AEs.<\/p>\n

Good to know but questions remain. There are already a few drugs on the market that have effects on the M2 receptor; we would have expected some\u00a0comparison data to put matters in perspective. Instead, much of the Tanaka paper is devoted to\u00a0investigations into QT prolongation which was not found to be an issue with omadacycline.\u00a0

It\u2019s always good to have some good news to share when you have to come out with problem data<\/span>.<\/p>\n<\/div>. QT prolongation has never\u00a0been an issue\u00a0with the tetracycline class of antibiotics, and\u00a0omadacycline is no exception.<\/p>\n

As is well known, QT prolongation was studied in great detail by Bayer when moxifloxacin (Avelox) was in development. To the company\u2019s credit, world-renowned experts were consulted to study the effects of moxifloxacin on the conduction system; indeed, during an Advisory Board session FDA reviewers were\u00a0complimentary of the way this issue was prospectively addressed and scientifically dissected by the company.<\/p>\n

In contrast, the studies of omadacycline’s effect on the cardiac M2 receptors\u00a0were all written up by Paratek insiders who \u2013 to the best of our knowledge \u2013 have no particular expertise in cardiology, cardiac physiology or pharmacology, or in muscarinic receptor research.\u00a0It remains to be seen whether the data (and the\u00a0benign assessment provided) will hold up to expert scrutiny.<\/p>\n

Will\u00a0omadacycline become the future control drug for M2 testing like moxifloxacin has become for TQTc studies? Unlikely, we\u00a0already have several other drugs that could be used for that purpose, like diphenhydramine and chlorpromazine.<\/p>\n

References:
\n<\/strong>[1]<\/a> K Tanaka.\u00a0 In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline.\u00a0 AAC 2016; 60: 5247
\n[2]<\/a> G Noel.\u00a0 A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Ef\ufb01cacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections.\u00a0 AAC 2012; 56: 5650<\/p>\n

Abbreviations:<\/strong><\/p>\n

ABSSSI \u00a0 \u00a0acute bacterial skin \/ skin-structure infection
\nTQTc \u00a0 \u00a0 \u00a0 \u00a0thorough QT study
\ncSSSI \u00a0 \u00a0 \u00a0complicated skin\/skin structure infection (an earlier version of ABSSSI)
\nM2 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 a (mainly cardiac)\u00a0muscarinic receptor<\/p>\n","protected":false},"excerpt":{"rendered":"

Several\u00a0interesting articles appeared recently which shed light on the efficacy of eravacycline and the safety of\u00a0omadacycline, both in Phase 3 and both in a head-to-head race to the market.\u00a0 Well, the term \u2018race\u2019 is bit of a stretch as both drugs have seen very significant delays in development. Omadacycline from Continue reading Timely New Information on Next-Generation Tetracyclines \u2013 Part 1: Omadacycline and Cardiac AEs<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2684,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[19,227,3,18],"tags":[1271,403,215,220,1730,842,1739,1731,1738,425,5,1583,1728,1743,47,1727,433,1732,434,1725,1726,713,1371,222,1106,1729,263,435,43,1740],"class_list":["post-2676","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-avelox","tag-bayer","tag-blood-pressure-increase","tag-cardiac-toxicity","tag-chlorpromazine","tag-csssi-study","tag-diphenhydramine","tag-eravacycline","tag-fda","tag-harald-reinhart","tag-m2-antagonist","tag-m2-receptor","tag-moxifloxacin","tag-muscarinic-receptor","tag-omadacycline","tag-omadacycline-aes","tag-paratek","tag-pk","tag-protein-binding","tag-ptk-0796","tag-qidp","tag-qt-prolongation","tag-qtc-prolongation","tag-tachycardia","tag-tetracycline","tag-tetraphase","tag-tigecycline","tag-tqtc-study"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?fit=649%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-Ha","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":689,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/04\/689\/some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study\/","url_meta":{"origin":2676,"position":0},"title":"Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study","author":"Harald","date":"August 4, 2014","format":false,"excerpt":"Solomkin et al. conclude that the efficacy and safety of eravacycline compares favorably to the control drug, ertapenem.[1]\u00a0 This top-level assessment is made with the usual caveats (insufficient statistical power, small sample size), but a few points deserve comment. Eravacycline is a fluorocycline; as a tetracycline derivative it follows into\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/08\/eravacycline-copy.jpg?fit=481%2C212&ssl=1&resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1168,"url":"https:\/\/allphasepharma.com\/dir\/2014\/12\/15\/1168\/the-circuitous-route-to-phase-3-another-chapter-in-the-fitful-development-of-ptk-0796\/","url_meta":{"origin":2676,"position":1},"title":"The Circuitous Route to Phase 3:\u00a0 Another Chapter in the Fitful Development of PTK-0796","author":"Harald","date":"December 15, 2014","format":false,"excerpt":"When antibiotics change hands, it can be a good thing.\u00a0 Small companies are often desperate to attract a partner with \u2018deep pockets\u2019 to help them finance an expensive late phase development but often have to give up control once\u00a0the honeymoon period is over.\u00a0 Such transitions can bring delays because new\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":2697,"url":"https:\/\/allphasepharma.com\/dir\/2016\/09\/19\/2697\/timely-new-information-on-next-generation-tetracyclines-part-2-eravacycline-and-protein-binding\/","url_meta":{"origin":2676,"position":2},"title":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 2: Eravacycline and Protein Binding","author":"Harald","date":"September 19, 2016","format":false,"excerpt":"A recent paper by Thabit describes a curious finding [1]. The authors measured total and free (i.e.,\u00a0nonprotein-bound) eravacycline levels at ascending doses in a mouse model. They found strikingly small increases in free drug levels when titrating up\u00a0total doses. 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