03291nas a2200445   4500000000100000008004100001260003400042653002100076653002100097653002000118653001700138653001300155100001000168700001300178700001300191700001500204700001500219700001300234700001500247700002200262700001400284700001500298700001400313700001400327700001200341700001300353700001300366700001900379700001100398700002100409700001200430700001400442700001600456700001400472245013600486856026000622300000700882520193100889022002502820       2025                            d  bOxford University Press (OUP)10aPharmacokinetics10aPharmacodynamics10afosravuconazole10aitraconazole10aMycetoma1 aChu W1 aFahal AH1 aAhmed ES1 aBakhiet SM1 aBakhiet OE1 aFahal LA1 aMohamed AA1 aMohamedelamin ESW1 aBahar MEN1 aAttalla HY1 aSiddig EE1 aMhmoud NA1 aMusa AM1 aOyieko P1 aEgondi T1 aBrüggemann RJ1 aHata K1 aStrub-Wourgaft N1 aAlves F1 aNyaoke BA1 aZijlstra EE1 aDorlo TPC00aPharmacokinetics and Pharmacodynamics of Fosravuconazole, Itraconazole and Hydroxyitraconazole in Sudanese Patients With Eumycetoma  uhttps://watermark.silverchair.com/jiaf279.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA2UwggNhBgkqhkiG9w0BBwagggNSMIIDTgIBADCCA0cGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMXgCAf6-LVoITfL-vAgEQgIIDGLLKLFFk0FKDSBzgIHfKX6Ya_P9Km41N5-xwHLvrA-m5OvC  a203 a<p><strong>Background</strong> 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.</p>

<p><strong>Methods</strong> Nonlinear mixed-effects modeling was used to develop population PK models in 52 patients receiving three daily loading doses followed by weekly fosravuconazole (200 mg or 300 mg) or twice daily itraconazole (total 400 mg), both over 12 months. Attainment of the in vitro MIC90 for M. mycetomatis was assessed, and the relationships between drug exposure, lesion size reduction, and complete cure were evaluated.</p>

<p><strong>Results</strong> Ravuconazole PK followed a two-compartment model with Michaelis-Menten elimination and a 63% (95%CI:38-90) bioavailability increase during the loading phase, leading to 75% higher exposure for a 50% dose increase. Itraconazole and hydroxyitraconazole were modeled jointly, with auto-inhibition 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 mg over 200 mg fosravuconazole.</p>

<p><strong>Conclusions</strong> Ravuconazole and itraconazole showed non-linear clearance with no clear exposure-response relationship. The 200 mg fosravuconazole dose is preferred for future use over 300 mg, as it lowers pill burden and enhances cost-effectiveness.</p>
  a0022-1899, 1537-6613