{"id":689,"date":"2014-08-04T18:18:56","date_gmt":"2014-08-04T22:18:56","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=689"},"modified":"2015-10-07T03:40:58","modified_gmt":"2015-10-07T07:40:58","slug":"some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/08\/04\/689\/some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study\/","title":{"rendered":"Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study"},"content":{"rendered":"
\"eravacycline\"<\/a>
eravacycline<\/figcaption><\/figure>\n

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.<\/p>\n

Eravacycline is a fluorocycline; as a tetracycline derivative it follows into the footsteps of doxycycline, tigecycline (Tygacil\u00ae \/ Wyeth) and omadacycline (Paratek).\u00a0 Hence, broad-spectrum activity against Acinetobacter and ESBL producers would be expected, in addition to broad coverage of Gram-positive, Gram-negative, atypical and anaerobe pathogens as is\u00a0typical for\u00a0the entire tetracycline class.<\/p>\n

A recognized liability of the tetracycline class is its propensity to cause nausea, vomiting\u00a0and abdominal pain.\u00a0 Doxycycline is not easy on the stomach, and neither is tigecycline.\u00a0 Not a side-effect profile that surgeons or patients that just underwent major abdominal surgery like to deal with.\u00a0 It is a significant side effect, not just a nuisance.<\/p>\n

In the case of tigecycline, this amounts to a dose-limiting toxicity [2] which resulted in suboptimal dosing to the point of underdosing.\u00a0 As we know, tigecycline was inferior to SOC in VAP patients, with increased mortality as a result.\u00a0 The dose in the HAP\/VAP trial was 100 mg IV (loading dose) followed by 50 mg IV q12h and probably too low. \u00a0The same dose was used for cSSSI, cIAI and CAP, infections with a rather high success rate for antibiotics old and new.<\/p>\n

If we have learned anything from 3 prior failures (the ceftibiprole, doripenem, tigecycline), it is the fact that HAP\/VAP is a tough proving ground for antibiotics.<\/p>\n

So, we will want to know precisely how eravacycline stacks up against SOC at tolerated dose levels.\u00a0 This is an AUC over MIC drug, so\u00a0it is\u00a0hoped that optimal dosing (based on PK\/PD modeling) is\u00a0not compromised by safety\/tolerability issues.<\/p>\n

In the Phase 2\u00a0trial, a\u00a0numerically higher rate of GI side effects was seen with the higher once-a-day dosing scheme compared to the lower dose and the comparator. \u00a0However, given the uneven randomization scheme (2:2:1) and small number of control cases on SOC\u00a0(N=30), efficacy comparisons are problematic. \u00a0This was a dose selection study first and foremost,\u00a0not\u00a0a comparison to SOC study.<\/p>\n

Hence, both the efficacy and safety of eravacycline will require confirmation in\u00a0pivotal\u00a0Phase 3 trials\u00a0which are now underway for cIAI and cUTI.<\/p>\n

In the Phase 2 trial eravacycline was dosed at either 1.5 mg\/kg q24h or at 1.0 mg\/kg q12h.\u00a0 In the Phase 3 IGNITE program, eravacycline is dosed with\u00a0the better tolerated 1.0 mg\/kg q12h regimen.[3]\u00a0 Such weight-based dosing may be a clever move on part of Tetraphase as it allows for some degree of dose normalization not doable with a fixed dose schedule.<\/p>\n

However, it will make the IV to PO transition quite difficult, assuming FDA insist on bioequivalent PO dosing for step-down therapy.<\/p>\n

Abbreviations:<\/strong>
\nHAP\/VAP \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 Hospital acquired, Ventilator-Associated Pneumonia
\nSOC \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0Standard of Care
\nAUC\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Area under the plasma concentration curve
\nPK\/PD\u00a0\u00a0\u00a0 \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Pharmacokinetic\/pharmacodynamic<\/p>\n

\n

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

[1] J. Solomkin.\u00a0 http:\/\/aac.asm.org\/content\/early\/2013\/12\/10\/AAC.01614-13.full.pdf
\n[2] G. Muralidharan.\u00a0 Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects. \u00a0Antimicrob. Agents Chemother. 2005; 49:220
\n[3] http:\/\/ir.tphase.com\/releasedetail.cfm?ReleaseID=862238<\/p>\n","protected":false},"excerpt":{"rendered":"

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 Continue reading Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":693,"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":[19,3],"tags":[198,429,436,442,354,82,355,432,428,427,425,441,350,5,438,439,430,433,434,39,1371,437,263,435,43,426,440],"class_list":["post-689","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","tag-acinetobacter","tag-antibiotics-blog","tag-bioequivalence","tag-cap","tag-ciai","tag-csssi","tag-cuti","tag-doripenem","tag-dose-finding","tag-doxycycline","tag-eravacycline","tag-ertapenem","tag-esbl","tag-fda","tag-gi-toxicity","tag-hapvap","tag-ignite","tag-omadacycline","tag-paratek","tag-pkpd","tag-qidp","tag-step-down-therapy","tag-tetracycline","tag-tetraphase","tag-tigecycline","tag-tygacil","tag-wyeth"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/08\/eravacycline-copy.jpg?fit=481%2C212&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-b7","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"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":689,"position":0},"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. The effect was rather dramatic: an increase in\u00a0protein binding from 12%\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Horserace Tigecycline Erava","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1958,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/24\/1958\/after-icaac-some-more-thoughts-on-eravacycline-in-cuti-and-ignite-2\/","url_meta":{"origin":689,"position":1},"title":"After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2","author":"Harald","date":"September 24, 2015","format":false,"excerpt":"When a well-designed pivotal Phase 3 trial fails to show NI, it demands an explanation.\u00a0 While awaiting the company\u2019s analysis of the data, many possible explanations are bandied about.\u00a0 So it was not surprising that the eravacycline cUTI study (IGNITE-2) was mentioned quite often during ICAAC 2015, in sessions and\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Erava2blog copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=700%2C400 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=1050%2C600 3x"},"classes":[]},{"id":2676,"url":"https:\/\/allphasepharma.com\/dir\/2016\/09\/13\/2676\/timely-new-information-on-next-generation-tetracyclines-part-1-omadacycline-and-cardiac-aes\/","url_meta":{"origin":689,"position":2},"title":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 1: Omadacycline and Cardiac AEs","author":"Harald","date":"September 13, 2016","format":false,"excerpt":"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\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Horserace Tigecycline Omada","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2142,"url":"https:\/\/allphasepharma.com\/dir\/2015\/11\/23\/2142\/eravacycline-conference-call-unrevealing-and-disappointing\/","url_meta":{"origin":689,"position":3},"title":"Eravacycline Conference Call: Unrevealing and Disappointing","author":"Harald","date":"November 23, 2015","format":false,"excerpt":"Whatever has become of investigative journalism?\u00a0 All we read after the Stifel conference call (11\/17\/2015) is descriptive rehash of information provided by Tetraphase at the conference.\u00a0 No probing questions that we thought investors would ask who just lost 80% of their money.\u00a0 No signs of analytical or strategic readjustment at\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\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=525%2C300 1.5x"},"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":689,"position":4},"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":2802,"url":"https:\/\/allphasepharma.com\/dir\/2016\/10\/18\/2802\/qidp-drug-update-part-1-an-updated-who-is-who\/","url_meta":{"origin":689,"position":5},"title":"QIDP Drug Update \u2013 Part 1: An Updated Who Is Who","author":"Harald","date":"October 18, 2016","format":false,"excerpt":"It is time for a new look at the field of QIDP drugs. 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