Pharmacokinetics and Pharmacodynamics of Fosravuconazole, Itraconazole, and Hydroxyitraconazole in Sudanese Patients With Eumycetoma
Abstract
BACKGROUND: 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.
METHODS: Nonlinear mixed-effects modeling was used to develop population PK models in 52 patients receiving 3 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 90% minimum inhibitory concentration (MIC90) for Madurella mycetomatis was assessed, and the relationships between drug exposure, lesion size reduction, and complete cure were evaluated.
RESULTS: Ravuconazole PK followed a 2-compartment model with Michaelis-Menten elimination and a 63% (95% confidence interval, 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 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…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 52 participants or records.
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