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 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.

Keywords: fosravuconazole; itraconazole; mycetoma; pharmacodynamics; pharmacokinetics.

Figure 1.

Predose plasma concentrations versus time. A, Measurement of ravuconazole in patients administered 200 mg (left) and 300 mg (right) fosravuconazole. B, Measurement of itraconazole (left) and hydroxyitraconazole (right) in patients administered itraconazole. The solid line represents the median value, while the shaded area indicates the interquartile range (25th to 75th percentiles).

Figure 2.

Final pharmacokinetics model. A, Ravuconazole. B, Itraconazole and hydroxyitraconazole. Abbreviations: C_central, concentration of the central compartment; CL, clearance; CL_m, clearance of metabolite OH-ITZ; CL_p, clearance ITZ; EC₅₀, itraconazole plus hydroxyitraconazole concentration (C_{ITZ + OH-ITZ}) at 50% of autoinhibition effect; E_max, maximum effect of autoinhibition; F, relative bioavailability; ITZ, itraconazole; k_a, rate of absorption; K_m, Michaelis-Menten constant; OH-ITZ, hydroxyitraconazole; Q, intercompartmental clearance; Vc, volume of distribution central compartment; V_m, volume of distribution for metabolite OH-ITZ; V_max, maximum velocity; V_p, volume of distribution.

Figure 3.

Estimated free drug concentrations of ravuconazole and itraconazole plus hydroxyitraconazole versus in vitro MIC₉₀. A, The dashed lines represent MIC₉₀ of 0.016 mg/L for ravuconazole [15]. The solid lines represents free drug concentration of ravuconazole (98% protein binding) with dose of fosravuconazole 200 mg (red) and 300 mg (blue). B, The dashed lines represent MIC₉₀ of 0.25 mg/L for itraconazole and hydroxyitraconazole [15]. The solid lines represents free drug concentration of combined itraconazole and hydroxyitraconazole with 96% (green) and 99% (orange) protein binding. Abbreviation: MIC₉₀, 90% minimum inhibitory concentration.

Figure 4.

Exposure-response relationships. A, Drug exposure versus complete cure at the end of treatment at 12 months based on individual treatment arms. The horizontal line within the box represents the median. The box indicates the IQR, spanning from the 25th to the 75th percentile. Whiskers extend to the most extreme data points within 1.5 times the IQR from the lower and upper quartiles. Complete cure was defined as absence of clinical evidence such as eumycetoma mass, sinus tract, or discharge; normal ultrasonography or magnetic resonance imaging examination of the eumycetoma site; or if a mass was present, negative fungal culture from a surgical biopsy from the former eumycetoma site [7]. B, Drug exposure versus the change in lesion size prior to surgery from baseline. The x-axis shows the AUC_0–6m for ravuconazole and itraconazole plus hydroxyitraconazole up to the 6-month surgical intervention. The y-axis represents the percentage change in lesion size relative to baseline, with negative values indicating a decrease and positive values indicating growth. The solid line represents the fitted linear regression model. The shaded area indicates the 95% confidence interval for the estimated regression line. Abbreviation: AUC, area under the curve; IQR, interquartile range.