Pharmacokinetics and Pharmacodynamics of Fosravuconazole, Itraconazole, and Hydroxyitraconazole in Sudanese Patients With Eumycetoma

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 between drug exposure and lesion size reduction or complete cure, indicating no additional benefit of 300 mg over 200 mg fosravuconazole.

CONCLUSIONS: Ravuconazole and itraconazole showed nonlinear 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. Clinical Trials Registration. NCT03086226.