{"id":1371,"date":"2015-04-14T13:01:27","date_gmt":"2015-04-14T17:01:27","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1371"},"modified":"2015-10-07T03:36:50","modified_gmt":"2015-10-07T07:36:50","slug":"cresemba-isavuconazole-not-just-another-azole","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/04\/14\/1371\/cresemba-isavuconazole-not-just-another-azole\/","title":{"rendered":"Cresemba \/ Isavuconazole: \u00a0Not Just Another Azole"},"content":{"rendered":"
\"Beta-cyclodextrin\"<\/a>
beta-cyclodextrin structure<\/figcaption><\/figure>\n

It is amazing how modifications to the azole structure have produced ever more potent, ever more useful antifungals.\u00a0 Ketoconazole had limited usability because of its many side effects related to off-target sterol synthesis inhibition, solubility (or lack thereof) and erratic absorption.\u00a0 Solublity was also an issue for itraconazole and posaconazole.\u00a0 Schering worked on posaconazole for more than a decade, trying to find a formulation suitable for more than just prophylactic use.<\/p>\n

And then there is Voriconazole (Vfend\u00ae), a drug we learned to love despite a long list of issues.\u00a0 It requires co-administration of a cyclodextrin (SBECD) to make the IV solution, well, soluble. \u00a0There is\u00a0a very long list of drug-drug interactions filling the pages of the Package Insert.<\/p>\n

Fluconazole (Diflucan\u00ae) was always the big exception: the oral drug had good bioavailability, and the IV formulation did not require any formulation wizardry.\u00a0 It led the azole chart of MVAs (Most Valuable Azoles) for more weeks than Elvis trumped the Billboard Hot 100 chart with ‘Hound Dog’.<\/p>\n

Companies like Janssen (ketoconazole and itraconazole) and Bayer (clotrimoxazole) worked on azole chemistry for many years.\u00a0 Both had a big stake in the field and knew about the potential of the class for mold infections.\u00a0 But progress was slow in coming until voriconazole became available.<\/p>\n

Compared to amphotericin B, voriconazole had a winning profile.\u00a0 Although only fungistatic (like all other azoles), it nevertheless proved to be as effective as the much more toxic AmB in the treatment of Aspergillus infections.\u00a0 This was nothing less than a breakthrough.\u00a0 The fact that it also covered Candida was of little significance.<\/p>\n

This March FDA approved isavuconazole (Cresemba\u00ae) for Aspergillus and Mucor infections.\u00a0 Hence, it is an appropriate time to compare both azoles side-by-side in an unbiased fashion.\u00a0 Below a tabulated comparative listing of core attributes which are important to practicing clinicians.<\/p>\n

\"Cresemba-pic\"<\/a><\/p>\n

The major drawback of voriconazole is side effect profile in general, and the drug-drug interactions in particular. \u00a0Doctors also need to be\u00a0on the look-out for CNS effects and warn patients in advance about visual disturbances.<\/p>\n

There is a lot to like about isavuconazole. \u00a0Importantly, the list of DDI and AEs is significantly shorter. \u00a0However, as always there are some big Rumsfeldian \u201cknown unknowns\u201d and \u201cunknown unknowns\u201d, the former we can address here.\u00a0 It is the limited data situation for Cresemba which is perhaps the main concern at this time.\u00a0 Hopefully, with the accrual of more data, Astellas \/ Basilea can build a more robust database of both efficacy and safety data and alleviate this concern.<\/p>\n

Prospective enrollment of Mucor and Aspergillosis cases into a well-controlled trial is an extremely difficult task.\u00a0 It is unrealistic to expect from sponsors that they engage in what could turn out to be a decade-long effort.\u00a0 It would make more sense to grant provisional approval based on interim data while continuing the recruitment effort.\u00a0 This way, interpretable data would be generated in the long run instead of having to deal with uninterpretable data comparing the test drug with historical controls. \u00a0Or no controls at all.<\/p>\n

Short quiz:<\/p>\n

    \n
  1. Did you know that cyt450 2C19 is the major cause\u00a0for voriconazole\u2019s DDI profile? This apparently was an ID Board question a few years ago.<\/li>\n
  2. Did you know that cyclodextran is classified as GRAS by FDA? The same cannot be said for SBECD, a novel version of beta-cyclodextran.<\/li>\n
  3. Which other azole was approved in the last 12 months? Actually, 3 azoles were approved: luliconazole (Luzu\u00ae) and efinaconazole (Jublia\u00ae), both for topical treatment of\u00a0tinea. \u00a0An IV formulation of posaconazole (Noxafil\u00ae) was approved for prophylaxis of Candida and Aspergillus infection this year.<\/li>\n
  4. Which other azole is co-formulated with cyclodextrin? You guessed right, it is itraconazole.<\/li>\n
  5. What other drugs use cyclodextrin for solubilization? More than we have space to list; there are at least 30 different compounds that are co-formulated with cyclodextrin to improve solubility or oral absorption.[1]<\/a><\/li>\n<\/ol>\n

     <\/p>\n

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

    GRAS\u00a0\u00a0\u00a0\u00a0 generally regarded as safe
    \nSBECD\u00a0\u00a0 sulfobutylether-\u03b2-cyclodextrin
    \nDDI \u00a0 \u00a0 \u00a0 \u00a0 drug-drug interactions<\/p>\n

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

    [1]<\/a> G Tiwari\u00a0 J Pharm Bioallied Sci. 2010; 2: 72
    \n[2] Package Insert, Cresemba
    \n[3] Package Insert, Vfend<\/p>\n","protected":false},"excerpt":{"rendered":"

    It is amazing how modifications to the azole structure have produced ever more potent, ever more useful antifungals.\u00a0 Ketoconazole had limited usability because of its many side effects related to off-target sterol synthesis inhibition, solubility (or lack thereof) and erratic absorption.\u00a0 Solublity was also an issue for itraconazole and posaconazole.\u00a0 Continue reading Cresemba \/ Isavuconazole: \u00a0Not Just Another Azole<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1377,"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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[140,19,3,18],"tags":[471,403,888,650,804,225,595,220,651,941,942,932,939,930,610,150,943,936,927,931,937,934,935,655,929,933,793,940,944,938,928],"class_list":["post-1371","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-interesting_facts","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-amphotericin-b","tag-antibiotic-blog","tag-aspergillosis","tag-aspergillus","tag-astellas","tag-azole","tag-basilea","tag-bayer","tag-candida","tag-clotrimoxazole","tag-cresemba","tag-cyclodextran","tag-diflucan","tag-efinaconazole","tag-isavuconazole","tag-itraconazole","tag-janssen","tag-jublia","tag-ketoconazole","tag-luliconazole","tag-lulu","tag-mucor","tag-noxafil","tag-pfizer","tag-posaconazole","tag-sbecd","tag-schering","tag-sporanox","tag-tinea","tag-vfend","tag-voriconazole"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/04\/Cresemba.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-m7","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2396,"url":"https:\/\/allphasepharma.com\/dir\/2016\/03\/23\/2396\/the-cresemba-candidemia-gamble-rien-ne-va-plus\/","url_meta":{"origin":1371,"position":0},"title":"The Cresemba Candidemia Gamble \u2013 Rien Ne Va Plus","author":"Harald","date":"March 23, 2016","format":false,"excerpt":"Isavuconazole is a potent triazole; like Voriconazole, it has garnered an indication for invasive aspergillosis. However, it failed where other azole antifungals succeeded: in a pivotal trial, not yet published, the drug was inferior to Caspofungin in the treatment of invasive candidiasis\/candidemia in non-neutropenic patients\u00a0[1]. To provide some background: in\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Crescemba Gamble copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1946,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/21\/1946\/allphase-pharma-the-first-100-blog-posts\/","url_meta":{"origin":1371,"position":1},"title":"ALLPHASE PHARMA – THE FIRST 100 BLOG POSTS","author":"Harald","date":"September 21, 2015","format":false,"excerpt":"After the first 100 blogs, it is appropriate to reflect on reader preferences.\u00a0 When I arbitrarily select a topic, it is not always clear whether what interests me also interests you. Since its start\u00a01\u00bd years ago, this blog has grown steadily in readership. \u00a0So we did a few things right\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"blog100 - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2205,"url":"https:\/\/allphasepharma.com\/dir\/2015\/12\/23\/2205\/qidp-antibiotics-2015-year-end-update\/","url_meta":{"origin":1371,"position":2},"title":"QIDP Antibiotics – 2015 Year-End Update","author":"Harald","date":"December 23, 2015","format":false,"excerpt":"Here an updated listing of all QIDP drugs we are aware of as of 12\/24\/2015. Today just\u00a0facts and numbers; we will provide an interpretation of the current landscape in upcoming blogs. There are\u00a058 drugs which garnered QIDP status and these are listed in the Main Table below. With the recent\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\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/QIDP-slider.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":2625,"url":"https:\/\/allphasepharma.com\/dir\/2016\/07\/13\/2625\/aspergillus_guideline-zip\/","url_meta":{"origin":1371,"position":3},"title":"Aspergillus_Guideline.ZIP","author":"Harald","date":"July 13, 2016","format":false,"excerpt":"Now, I know we should not make light of any IDSA Guidelines, far from it. This latest, the Aspergillus Guideline [1], like others before, is a thoughtful document which reviews the newest information and reflects expert authoritative thinking on the subject. It also is a hefty 60 pages long, as\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Rules-Regx-Guidelines - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1800,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/01\/1800\/qidp-drugs-4th-edition\/","url_meta":{"origin":1371,"position":4},"title":"QIDP Drugs – 4th Edition","author":"Harald","date":"August 1, 2015","format":false,"excerpt":">>> For the latest QIDP list, please click HERE \u00a0<<< Since our\u00a0last QIDP blog from April 8, 2015, several new drugs have made the list which now includes 41 compounds. 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