{"id":1561,"date":"2015-06-17T04:44:08","date_gmt":"2015-06-17T08:44:08","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1561"},"modified":"2015-10-07T03:36:00","modified_gmt":"2015-10-07T07:36:00","slug":"treating-gc-in-the-face-of-dwindling-antibiotic-options-2","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/06\/17\/1561\/treating-gc-in-the-face-of-dwindling-antibiotic-options-2\/","title":{"rendered":"Treating GC in the Face of Dwindling Antibiotic Options \u2013 (2)"},"content":{"rendered":"

For GC antibiotics, the development path looks like a trip down the road less traveled, leading into some uncharted territory.<\/p>\n

Let\u2019s take Melinta\u2019s statement\u00a0[1]<\/a> at face value according to which the single 900 mg dose of delafloxacin failed because of “insufficient efficacy”.<\/p>\n

So, what then determines efficacy? \u00a0Delafloxacin’s MIC90<\/sub> was between 0.125-0.5 mg\/L which should have made it an excellent drug. \u00a0Besides organism MIC, one would think that PK \/ PD had something to do with\u00a0organism eradication.\u00a0 As the primary efficacy endpoint in the\u00a0recent FDA Guidance is a negative culture at Day 3-7 [2]<\/a>, issues related to relapse or reinfection won’t dilute\u00a0the success rate.<\/p>\n

Because GC treatment is one-time\u00a0therapy, a drug with long half-life has a higher chance to deliver.\u00a0 As the gonococcus is an intracellular pathogen, tissue penetration may also be an important feature.<\/p>\n

Besides\u00a0delafloxacin,\u00a0there are only 2 drugs at an\u00a0advanced stage of clinical\u00a0development:\u00a0AZD-0914 and solithromycin\/CEM-101. \u00a0For both it will be\u00a0important to get the PK\/PD relationship right.<\/p>\n

Some older literature have addressed the MIC \/ PK \/ efficacy relationship. \u00a0Moran et al, based on an extensive data review, provides a simple formula:<\/p>\n

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

What he terms \u2018therapeutic time\u2019, is in essence T> 4x MIC90 . <\/sub>His analysis concludes\u00a0that for a drug to be effective against urogenital GC it has to provide exposure for >10 hours above 4x the MIC90<\/sub> <\/span>[3]<\/a>.<\/p>\n

So, let\u2019s put this formula to use with existing information for our candidate drugs:\"GC<\/a><\/p>\n

 <\/p>\n

It is clear that both ceftriaxone and delafloxacin have no problem achieving \u2018therapeutic times\u2019 much longer than 10 hours.\u00a0 So, the formula is not holding up here.\u00a0 Only when factoring in the unbound fraction, the T> 4x MIC90<\/sub> drops below 10. But why would it affect delafloxacin and\u00a0not ceftriaxone which – as we know – has retained full activity despite a very small unbound free active fraction?<\/p>\n

What a pity: yet another formula which is doing well for retrospective analyses but not so much for forecasting. \u00a0You could call it a validation failure. \u00a0Or, for the more cynically inclined: Past performance is not a guarantee for future success.<\/em><\/p>\n

WITH THIS MAJOR\u00a0CAVEAT, let\u2019s move on to solithromycin for which the formula paints a very dismal picture indeed: here the PK parameters predict only 4 hours of T> 4x MIC90<\/sub>. \u00a0In addition, the drug has a very small\u00a0unbound fraction. \u00a0We already heard of\u00a0tolerability concerns: The dose was recently reduced (from 1200mg to 1000mg) indicating that\u00a0nausea\/vomiting\u00a0has been an issue, is an issue, and will continue to be an issue.<\/p>\n

Our last attempt to apply Moran\u2019s formula:\u00a0AZD-0914. \u00a0This new gyrase\/topoisomerase inhibitor is now being developed by Entasis Therapeutics, an AstraZeneca\u2019s spin-off . Insufficient PK information in the public domain makes it difficult to use Moran\u2019s formula, so it is anyone\u2019s guess how this drug compares to the other newcomers. \u00a0But it looks better than solithromycin assuming the\u00a0Cmax is >\u00a04 mg\/L (which would bring it over the 10 h threshold).<\/p>\n

Which seems quite doable given the whopping dose of 3 g orally.<\/p>\n

References:
\n<\/strong>[1]<\/a> http:\/\/www.melinta.com\/news.php?c=41
\n[2]<\/a> FDA Guidance June 2014: Uncomplicated Gonorrhea
\n[3]<\/a> J Moran CID 1995;20 (Suppl 1): S47<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

For GC antibiotics, the development path looks like a trip down the road less traveled, leading into some uncharted territory. Let\u2019s take Melinta\u2019s statement\u00a0[1] at face value according to which the single 900 mg dose of delafloxacin failed because of “insufficient efficacy”. So, what then determines efficacy? \u00a0Delafloxacin’s MIC90 was Continue reading Treating GC in the Face of Dwindling Antibiotic Options \u2013 (2)<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1571,"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":[19,3,18],"tags":[403,609,265,816,1010,819,236,1062,5,1065,1063,599,813,39,1371,827,468,993,1064],"class_list":["post-1561","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-antibiotic-blog","tag-azd-0914","tag-cefixime","tag-ceftriaxone","tag-cem-101","tag-cempra","tag-delafloxacin","tag-entasis-therapeutics","tag-fda","tag-gc","tag-gyrase-inhibitor","tag-melinta","tag-n-gonorrhoeae","tag-pkpd","tag-qidp","tag-rocephin","tag-solithromycin","tag-suprax","tag-topoisomerase-inhibitor"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/06\/GC-slider-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-pb","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1254,"url":"https:\/\/allphasepharma.com\/dir\/2015\/02\/02\/1254\/a-go-no-go-decision-delafloxacin-stumbles-in-gonorrhea-study\/","url_meta":{"origin":1561,"position":0},"title":"A GO \/ NO GO decision:\u00a0 Delafloxacin Stumbles in Gonorrhea Study","author":"Harald","date":"February 2, 2015","format":false,"excerpt":"The treatment history of N. gonorrhoeae makes for fascinating reading.\u00a0 This organism has always been able to keep the upper hand in the war of bug versus drug.\u00a0 Once susceptible to sulfa drugs, to penicillin, tetracyclines and fluoroquinolones, it sequentially become resistant in the matter of a decade to every\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"mic-2","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/mic-2.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":3238,"url":"https:\/\/allphasepharma.com\/dir\/2017\/03\/21\/3238\/gc-therapy-shooting-stars\/","url_meta":{"origin":1561,"position":1},"title":"GC Therapy – \u00a0Shooting for the Stars","author":"Harald","date":"March 21, 2017","format":false,"excerpt":"Besides ceftriaxone (CTRIAX), cefixime and spectinomycin we have no other highly effective single-dose treatment regimens for urogenital GC. Failures of all 3 drugs have been described but remain rare, can be overcome with higher doses of CTRIAX (1 g instead of 250 mg IM) or with azithromycin combination therapy. Worse\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\/2017\/03\/GC-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":157,"url":"https:\/\/allphasepharma.com\/dir\/2014\/04\/22\/157\/antibiotics-with-qidp-designation\/","url_meta":{"origin":1561,"position":2},"title":"Antibiotics with QIDP Designation – – – Updated 9-30-14","author":"Harald","date":"April 22, 2014","format":false,"excerpt":"For the latest QIDP listing, please click HERE \u00a0 Since\u00a0FDA issued the QIDP designation in 2012, many companies have requested this important 'label'. \u00a0Which should not come as a surprise: QIDP status confers significant benefits - and there is no downside. While an official FDA list of drugs that have\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\/04\/FDA-GAIN-LPAD-banner-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\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":1488,"url":"https:\/\/allphasepharma.com\/dir\/2015\/05\/26\/1488\/treating-gc-in-the-face-of-dwindling-antibiotic-options-1\/","url_meta":{"origin":1561,"position":3},"title":"Treating GC in the Face of Dwindling Antibiotic Options \u2013 (1)","author":"Harald","date":"May 26, 2015","format":false,"excerpt":"Looking across the Northern border it is clear that CDC Guidelines are not universally followed even in North America. Public Health Canada still recommends cefixime for uncomplicated gonorrhea (GC), albeit at the high single oral dose of 800 mg\u00a0[1]. 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