{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:03:06Z","timestamp":1791892986906,"version":"4.3.4"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013996","name":"Global Health Innovative, Technology Fund","doi-asserted-by":"crossref","award":["G2017\u2013106"],"award-info":[{"award-number":["G2017\u2013106"]}],"id":[{"id":"10.13039\/501100013996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007729","name":"Dutch Ministry of Foreign Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009131","name":"Swiss Agency for Development and Cooperation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009131","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Republic and Canton of Geneva, International Solidarity Service"},{"name":"M\u00e9decins Sans Fronti\u00e8res International"},{"name":"M\u00e9decins Sans Fronti\u00e8res Switzerland"},{"name":"UK International Development"},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["VR 2022\u201301251"],"award-info":[{"award-number":["VR 2022\u201301251"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The first clinical trial on eumycetoma was recently conducted in Sudan, comparing oral fosravuconazole, prodrug of active ravuconazole, with the standard-of-care oral itraconazole. Building on this trial, the present study aimed to characterize the pharmacokinetics-pharmacodynamics (PK-PD) of ravuconazole, itraconazole, and hydroxyitraconazole in patients with eumycetoma and guide selection of either a 200-mg or 300-mg dose of fosravuconazole.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Nonlinear mixed-effects modeling was used to develop population PK models in 52 patients receiving 3 daily loading doses followed by weekly fosravuconazole (200\u2005mg or 300\u2005mg) or twice-daily itraconazole (total 400\u2005mg), both over 12 months. Attainment of the in vitro 90% minimum inhibitory concentration (MIC90) for Madurella mycetomatis was assessed, and the relationships between drug exposure, lesion size reduction, and complete cure were evaluated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Ravuconazole PK followed a 2-compartment model with Michaelis-Menten elimination and a 63% (95% confidence interval, 38%\u201390%) bioavailability increase during the loading phase, leading to 75% higher exposure for a 50% dose increase. Itraconazole and hydroxyitraconazole were modeled jointly, with autoinhibition of itraconazole metabolism. Free ravuconazole remained above the MIC90 throughout the entire 12-month treatment period, while free itraconazole never reached the MIC90. Despite a large range in antifungal exposure, no significant relationships were found between drug exposure and lesion size reduction or complete cure, indicating no additional benefit of 300\u2005mg over 200\u2005mg fosravuconazole.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Ravuconazole and itraconazole showed nonlinear clearance with no clear exposure-response relationship. The 200\u2005mg fosravuconazole dose is preferred for future use over 300\u2005mg, as it lowers pill burden and enhances cost-effectiveness.<\/jats:p>\n                  <jats:p>Clinical Trials Registration. NCT03086226.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf279","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T04:59:20Z","timestamp":1748408360000},"page":"e518-e528","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetics and Pharmacodynamics of Fosravuconazole, Itraconazole, and Hydroxyitraconazole in Sudanese Patients With Eumycetoma"],"prefix":"10.1093","volume":"232","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-8807","authenticated-orcid":false,"given":"Wan-Yu","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Uppsala University , Uppsala ,","place":["Sweden"]},{"name":"Department of Pharmacy and Pharmacology, Netherlands Cancer Institute , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H","family":"Fahal","sequence":"additional","affiliation":[{"name":"Mycetoma Research Center, University of 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