{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:55:13Z","timestamp":1790009713223,"version":"4.0.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T00:00:00Z","timestamp":1568678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Defense Medical Research and Development Program","award":["W81XWH-15-2-0019"],"award-info":[{"award-number":["W81XWH-15-2-0019"]}]},{"name":"US Army Medical Research Acquisition Activity","award":["21702-5014"],"award-info":[{"award-number":["21702-5014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aspergillus spp. infections remain a global concern, with \u223c30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg\/kg after 5 days of QD administration (155 and 1033 \u03bcg*h\/ml, respectively), with a further increase with 40 mg\/kg BID dosing (1354 \u03bcg*h\/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 \u03bcg\/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg\/kg, intermediate decreases at QD 20 mg\/kg and maximum or near maximum decreases at 40 mg\/kg QD and BID. The PK\/PD relationships of AUCfree\/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg\/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.<\/jats:p>","DOI":"10.1093\/mmy\/myz092","type":"journal-article","created":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T03:16:54Z","timestamp":1566443814000},"page":"505-513","source":"Crossref","is-referenced-by-count":21,"title":["The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis"],"prefix":"10.1093","volume":"58","author":[{"given":"E P","family":"Garvey","sequence":"first","affiliation":[{"name":"Viamet Pharmaceuticals, Inc., Durham, NC 27703"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A D","family":"Sharp","sequence":"first","affiliation":[{"name":"Evotec UK Ltd., Macclesfield, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P A","family":"Warn","sequence":"first","affiliation":[{"name":"Evotec UK Ltd., Macclesfield, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C M","family":"Yates","sequence":"first","affiliation":[{"name":"Viamet Pharmaceuticals, Inc., Durham, NC 27703"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Atari","sequence":"first","affiliation":[{"name":"Cyprotex Discovery Ltd. Macclesfield, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Thomas","sequence":"first","affiliation":[{"name":"Cyprotex Discovery Ltd. Macclesfield, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R J","family":"Schotzinger","sequence":"first","affiliation":[{"name":"Viamet Pharmaceuticals, Inc., Durham, NC 27703"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,17]]},"reference":[{"key":"2020053120001397200_bib1","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1016\/j.jinf.2014.07.011","article-title":"The biology of pulmonary aspergillus infections","volume":"69","author":"Warris","year":"2014","journal-title":"J Infect"},{"key":"2020053120001397200_bib2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1093\/mmy\/myw114","article-title":"Invasive aspergillosis in acute myeloid leukemia: are we making progress in reducing mortality","volume":"55","author":"Dragonetti","year":"2017","journal-title":"Med Mycol"},{"key":"2020053120001397200_bib3","doi-asserted-by":"crossref","first-page":"E57","DOI":"10.3390\/jof3040057","article-title":"Global and multi-national prevalence of fungal diseases-estimate precision","volume":"3","author":"Bongomin","year":"2017","journal-title":"J Fungi"},{"key":"2020053120001397200_bib4","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bcp.2016.11.019","article-title":"Antifungals","volume":"133","author":"Campoy","year":"2017","journal-title":"Biochem Pharmacol"},{"key":"2020053120001397200_bib5","doi-asserted-by":"crossref","first-page":"E98","DOI":"10.3390\/jof4030098","article-title":"Treatment of aspergillosis","volume":"4","author":"Jenks","year":"2018","journal-title":"J Fungi"},{"key":"2020053120001397200_bib6","first-page":"135","article-title":"Fundamental concepts of azole compounds and triazole antifungals: a beginner's review","volume":"37","author":"Mart\u00ednez-Mat\u00edas","year":"2018","journal-title":"P R Health Sci J"},{"key":"2020053120001397200_bib7","first-page":"149","article-title":"Clinical hepatotoxicity associated with antifungal agents","volume":"16","author":"Kyriakidis","year":"2017","journal-title":"Expert Opin Drug Saf"},{"key":"2020053120001397200_bib8","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1111\/imj.12600","article-title":"Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014","volume":"44","author":"Chau","year":"2014","journal-title":"Intern Med J"},{"key":"2020053120001397200_bib9","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/jac\/dkx029","article-title":"Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations","volume":"72","author":"Stott","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"2020053120001397200_bib10","doi-asserted-by":"crossref","first-page":"779","DOI":"10.2165\/0003088-200847120-00003","article-title":"The enzymatic basis of drug-drug interactions with systemic triazole antifungals","volume":"47","author":"Nivoix","year":"2008","journal-title":"Clin Pharmacokinet"},{"key":"2020053120001397200_bib11","doi-asserted-by":"crossref","DOI":"10.1111\/tid.12751","article-title":"Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4","volume":"19","author":"Groll","year":"2017","journal-title":"Transpl Infect Dis"},{"key":"2020053120001397200_bib12","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1016\/j.bmcl.2017.06.037","article-title":"Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors","volume":"27","author":"Yates","year":"2017","journal-title":"Bioorg Med Chem Lett"},{"key":"2020053120001397200_bib13","doi-asserted-by":"crossref","first-page":"e00570","DOI":"10.1128\/AAC.00570-17","article-title":"Crystal structure of the new investigational drug candidate VT-1598 in complex with Aspergillus fumigatus sterol 14\u03b1-demethylase provides insights into its broad-spectrum antifungal activity","volume":"61","author":"Hargrove","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2020053120001397200_bib14","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1093\/jac\/dkx410","article-title":"The fungal specific Cyp51 inhibitor VT-1598 demonstrates potent in vitro activity against Candida and Cryptococcus species, endemic fungi, including Coccidioides species, Aspergillus species, and Rhizopus arrhizus","volume":"73","author":"Wiederhold","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2020053120001397200_bib15","doi-asserted-by":"crossref","first-page":"e02258","DOI":"10.1128\/AAC.02258-17","article-title":"The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis","volume":"62","author":"Wiederhold","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2020053120001397200_bib16","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1093\/jac\/dky242","article-title":"The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis","volume":"73","author":"Garvey","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2020053120001397200_bib17","doi-asserted-by":"crossref","first-page":"e02233","DOI":"10.1128\/AAC.02233-18","article-title":"The fungal Cyp51-specific inhibitor VT-1598 demonstrates in vitro and in vivo activity against Candida auris","volume":"63","author":"Wiederhold","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2020053120001397200_bib18","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1093\/jac\/dky170","article-title":"VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice","volume":"73","author":"Break","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2020053120001397200_bib19","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1128\/AAC.01279-12","article-title":"Posaconazole pharmacodynamic target determination against wild-type and Cyp51 mutant isolates of Aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis","volume":"57","author":"Lepak","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"2020053120001397200_bib20","doi-asserted-by":"crossref","first-page":"6284","DOI":"10.1128\/AAC.01355-13","article-title":"Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus","volume":"57","author":"Lepak","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"2020053120001397200_bib21","volume-title":"Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi\u2013Second Edition: Approved Standard M38A2","author":"Clinical and Laboratory Standards Institute","year":"2008"},{"key":"2020053120001397200_bib22","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.ijantimicag.2009.09.029","article-title":"Activity of aminocandin (IP960; HMR3270) compared with amphotericin B, itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus","volume":"35","author":"Warn","year":"2010","journal-title":"Int J Antimicrob Agents"},{"key":"2020053120001397200_bib23","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1093\/infdis\/jir023","article-title":"Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy","volume":"203","author":"Howard","year":"2011","journal-title":"J Infect Dis"},{"key":"2020053120001397200_bib24","doi-asserted-by":"crossref","first-page":"e40022","DOI":"10.1371\/journal.pone.0040022","article-title":"A MIQE-compliant real-time PCR assay for Aspergillus detection","volume":"7","author":"Johnson","year":"2012","journal-title":"PLoS One"},{"key":"2020053120001397200_bib25","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.2174\/13816128113199990332","article-title":"Pharmacodynamics and pharmacokinetics of antifungals for treatment of invasive aspergillosis","volume":"19","author":"Bellmann","year":"2013","journal-title":"Curr Pharm Des"},{"key":"2020053120001397200_bib26","doi-asserted-by":"crossref","first-page":"a019653","DOI":"10.1101\/cshperspect.a019653","article-title":"Antifungal pharmacokinetics and pharmacodynamics","volume":"5","author":"Lepak","year":"2014","journal-title":"Cold Spring Harb Perspect Med"}],"container-title":["Medical Mycology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mmy\/article-pdf\/58\/4\/505\/33196623\/myz092.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mmy\/article-pdf\/58\/4\/505\/33196623\/myz092.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T02:55:47Z","timestamp":1664160947000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mmy\/article\/58\/4\/505\/5571192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,17]]},"references-count":26,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,9,17]]},"published-print":{"date-parts":[[2020,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/mmy\/myz092","relation":{},"ISSN":["1369-3786","1460-2709"],"issn-type":[{"value":"1369-3786","type":"print"},{"value":"1460-2709","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6]]},"published":{"date-parts":[[2019,9,17]]}}}