{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:51:52Z","timestamp":1791219112436,"version":"4.1.0"},"reference-count":27,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2018,4,1]],"date-time":"2018-04-01T00:00:00Z","timestamp":1522540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100017467","name":"Amplyx","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017467","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic\/pharmacodynamic (PK\/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for\n Candida albicans<\/jats:named-content>\n (\n n<\/jats:italic>\n = 5),\n C. glabrata<\/jats:named-content>\n (\n n<\/jats:italic>\n = 5), and\n C. auris<\/jats:named-content>\n (\n n<\/jats:italic>\n = 4). MIC values ranged from 0.002 to 0.03 mg\/liter for\n C. albicans<\/jats:named-content>\n , from 0.008 to 0.06 mg\/liter for\n C. glabrata<\/jats:named-content>\n , and from 0.004 to 0.03 mg\/liter for\n C. auris<\/jats:named-content>\n . Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg\/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration (\n C<\/jats:italic>\n max<\/jats:sub>\n ) values of 0.46 to 15.6 mg\/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC\n 0\u2013inf<\/jats:sub>\n ) values of 0.87 to 70.0 mg \u00b7 h\/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against\n C. albicans<\/jats:named-content>\n K1, with total doses ranging from 4 to 1,024 mg\/kg\/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK\/PD index best correlated with efficacy on the basis of the reduction in the number of CFU\/kidney at 24 h. The 24-h free-drug AUC\/MIC ratio (\n f<\/jats:italic>\n AUC\n 0\u201324<\/jats:sub>\n \/MIC) was the PK\/PD index that best correlated with efficacy (coefficient of determination [\n R<\/jats:italic>\n 2<\/jats:sup>\n ] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg\/kg of APX001 administered every 6 h for a 24-h duration with\n C. albicans<\/jats:named-content>\n and a 96-h study duration with\n C. glabrata<\/jats:named-content>\n and\n C. auris<\/jats:named-content>\n . The dose required to achieve 50% of the maximum effect (ED\n 50<\/jats:sub>\n ) and stasis\n f<\/jats:italic>\n AUC\/MIC targets were as follows: for\n C. albicans<\/jats:named-content>\n , 3.67 \u00b1 3.19 and 20.60 \u00b1 6.50, respectively; for\n C. glabrata<\/jats:named-content>\n , 0.38 \u00b1 0.21 and 1.31 \u00b1 0.27, respectively; and for\n C. auris<\/jats:named-content>\n , 7.14 \u00b1 4.54 and 14.67 \u00b1 8.30, respectively. The present studies demonstrated\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n APX001A and APX001 potency, respectively, against\n C. albicans<\/jats:named-content>\n ,\n C. glabrata<\/jats:named-content>\n , and\n C. auris.<\/jats:named-content>\n These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC\/MIC ratio target for\n C. glabrata<\/jats:named-content>\n suggests that species-specific susceptibility breakpoints should be explored.\n <\/jats:p>","DOI":"10.1128\/aac.02542-17","type":"journal-article","created":{"date-parts":[[2018,1,27]],"date-time":"2018-01-27T11:29:45Z","timestamp":1517052585000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":57,"title":["In Vivo<\/i>\n Pharmacokinetics and Pharmacodynamics of APX001 against Candida spp. in a Neutropenic Disseminated Candidiasis Mouse Model"],"prefix":"10.1128","volume":"62","author":[{"given":"Miao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Lepak","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"VanScoy","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Schenectady, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin C.","family":"Bader","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Schenectady, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Marchillo","sequence":"additional","affiliation":[{"name":"William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Vanhecker","sequence":"additional","affiliation":[{"name":"William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Ambrose","sequence":"additional","affiliation":[{"name":"Institute for Clinical Pharmacodynamics, Schenectady, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Andes","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA"},{"name":"William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2016.06.029"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/2047-783X-16-4-187"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00029-06"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/599039"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1315399"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02117-09"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhin.2016.08.004"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw696"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-017-0805-2"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myw060"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2012.06798.x"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00731-11"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00366-11"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00291-11"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00570-11"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2011.05.001"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1086\/516284"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.9.2116"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.4.1193-1199.2003"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.10.3165-3169.2003"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.1.137-142.2004"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01430-10"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00478-08"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01584-09"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01061-07"},{"key":"e_1_3_1_27_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing of yeasts","author":"Clinical and Laboratory Standards Institute","year":"2008","unstructured":"Clinical and Laboratory Standards Institute. 2008. 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