{"id":2697,"date":"2016-09-19T06:07:35","date_gmt":"2016-09-19T10:07:35","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2697"},"modified":"2025-09-20T19:19:52","modified_gmt":"2025-09-21T01:19:52","slug":"timely-new-information-on-next-generation-tetracyclines-part-2-eravacycline-and-protein-binding","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/09\/19\/2697\/timely-new-information-on-next-generation-tetracyclines-part-2-eravacycline-and-protein-binding\/","title":{"rendered":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 2: Eravacycline and Protein Binding"},"content":{"rendered":"

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

A recent paper by Thabit describes a curious finding [1]<\/a>. 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.<\/p>\n

The effect was rather dramatic: an increase in\u00a0protein binding from 12% to 93% (yes, ninety-three percent!) was observed. Obviously,\u00a0higher doses of eravacycline resulted in proportionally higher degrees of protein binding, eventually reaching\u00a0a plateau. In other words, an atypical non-linear exposure curve was seen.<\/p>\n

This is a problematic feature; after all, one would like\u00a0to achieve adequate free drug<\/u> levels to penetrate tissues as well as reach and kill microbes that are not in the blood stream. Remember, it is free drug concentration and free AUC\/MIC ratio that are key determinants for tetracycline efficacy.\u00a0

<\/p>\n

Free drug concentration and free AUC\/MIC ratio are key determinants for tetracycline efficacy<\/span><\/p>\n<\/div><\/p>\n

As a matter of fact, blood levels of\u00a0tetracyclines are quite low even with IV dosing, and rhe same is true\u00a0for eravacycline. PK data from a Phase 1\u00a0study conducted by Connors\u00a0[3]<\/a>\u00a0confirms a rather flat concentration-time curve\u00a0(see below):<\/p>\n

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

Table<\/strong>: Eravacycline PK – adapted from Ref [3]<\/p>\n

With a peak fCmax<\/span>\u00a0of only 0.185 mg\/L, blood and tissue levels are clearly well below the MIC90<\/sub> values of many pathogens, which for the most part fall into the 0.25-1.0 mg\/L range\u00a0[2]<\/a>. \u00a0This makes clinicians\u00a0uneasy who do not fully subscribe to the\u00a0PK\/PD mantra, which for tetracyclines tells us that Cmax\u00a0<\/span>is not the best predictor of efficacy and fAUC\/MIC is all that matters.<\/p>\n

Eravacycline\u2019s favorable fAUC\/MIC ratio is\u00a0driven primarily by a\u00a0long T\u00bd in PK\/PD calculations, so we\u00a0hope that the infecting pathogens ‘understand’ this concept and ‘behave’ accordingly. The drug\u00a0also has\u00a0a\u00a0rather\u00a0large VD ,\u00a0<\/sub>which provides significant intracellular levels and may boost efficacy.<\/p>\n

This is all well and good, but intracellular levels matter\u00a0when the action\u00a0is also intracellular (like\u00a0for Neisseriae, Chlamydophila, Legionellae and a few others) but not for most other pathogens, including those causing pneumonia which reside in the extracellular space.<\/p>\n

What is gnawing on us is that PK\/PD analysis was wrong regarding\u00a0the dose selection for the\u00a0IGNITE2 (cUTI) study. This is the infamous Phase 3 study that failed to show non-inferiority to\u00a0levofloxacin, the comparator drug. Such mishaps are not supposed to happen in this enlightened age. \u00a0But – to be fair – nothing is ever just black or\u00a0white, and dose selection still is\u00a0a bit\u00a0of an art form.<\/p>\n

<\/p>\n

Could it be that PK\/PD models favored\u00a0higher doses, but the company still chose to take a calculated risk with a lower but per chance suboptimal cUTI dose?
\nWe do\u00a0hope that this was not the case here, but stranger things have happened before<\/span><\/p>\n<\/div>\n

Now back to protein binding. With\u00a0a drug like eravacycline, the described\u00a0effect on protein binding could have a negative impact on efficacy. Doses of 1 mg\/kg q12h – infused over 1 hour – were used\u00a0in IGNITE1, the pivotal cIAI trial and found to be efficacious. However,\u00a0a slightly lower dose employed in the cUTI trial did not make the grade. This all points to a very delicate balancing act as far as dosing is concerned.<\/p>\n

We would not go so far as to blame the recently failed cUTI trial on this phenomenon alone, although it may have been a contributing factor. Tetraphase certainly has not provided a satisfactory explanation for this.<\/p>\n

This paradoxical effect on protein binding, so different from other antibiotic drug classes, has already been described in\u00a0tigecycline and other tetracyclines, but it is an oddity, nonetheless [3]<\/a>,[4]<\/a>. \u00a0Are there other drugs that behave similarly? In our admittedly cursory search we came across none. This phenomenon may deserve further scrutiny.<\/p>\n

Time for us to check if the PK profile of omadacycline has similarly atypical\u00a0protein binding characteristics. Well, according to a recent poster, omadacycline behaves like\u00a0a different animal: Villano et al. report\u00a0concentration-independent protein binding of approx. 21%. This translates into 79% of unbound drug, much different from other tetracyclines which are usually highly protein-bound [5]<\/a>.<\/p>\n

Advantage Omadacycline!<\/p>\n

 <\/p>\n

References:
\n<\/strong>[1]<\/a> A Thabit. Eravacycline Pharmacokinetics and Challenges in De\ufb01ning Humanized Exposure In Vivo.\u00a0 AAC 2016; 60: 5072
\n[2]<\/a> G Zhanel. Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent.\u00a0 Drugs 2016; 76:567
\n[3]<\/a> K Connors. Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women.\u00a0 AAC\u00a0 2014;58:2113
\n[4]<\/a> R Singh. Plasma Protein binding of eravacycline in mouse, rat, rabbit, cynomolgus monkey, African green monkey and human using microdialysis [abstract no. A-015 plus poster]. 53rd ICAAC; 201
\n[5]<\/a> S Villano.\u00a0 In-vitro Protein Binding with Omadacycline, a First in Class Aminomethylcycline Antibiotic.\u00a0 ASM Microbe Poster 518, 2016<\/p>\n","protected":false},"excerpt":{"rendered":"

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% Continue reading Timely New Information on Next-Generation Tetracyclines \u2013 Part 2: Eravacycline and Protein Binding<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2700,"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":[1271,403,1733,1735,354,355,425,1737,1583,1741,1742,1736,516,213,1734,433,434,1725,39,1726,713,263,435,43,1330,426],"class_list":["post-2697","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-aucmic","tag-chlamydophila","tag-ciai","tag-cuti","tag-eravacycline","tag-free-drug-concentration","tag-harald-reinhart","tag-ignite1","tag-ignite2","tag-legionella","tag-levaquin","tag-levofloxacin","tag-neisseria","tag-omadacycline","tag-paratek","tag-pk","tag-pkpd","tag-protein-binding","tag-ptk-0796","tag-tetracycline","tag-tetraphase","tag-tigecycline","tag-tp-434","tag-tygacil"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?fit=649%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-Hv","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"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":2697,"position":0},"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":689,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/04\/689\/some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study\/","url_meta":{"origin":2697,"position":1},"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":2142,"url":"https:\/\/allphasepharma.com\/dir\/2015\/11\/23\/2142\/eravacycline-conference-call-unrevealing-and-disappointing\/","url_meta":{"origin":2697,"position":2},"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":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":2697,"position":3},"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. 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