Comparative Pharmacokinetics of Intravenous Versus Oral Formulations of a Novel Antifungal Agent
DOI:
https://doi.org/10.5281/zenodo.22664603Keywords:
antifungal pharmacokinetics, oral bioavailability, triazole formulation, IV-to-oral switch therapy, non-compartmental analysisAbstract
Background: Triazole antifungals are valued for their ability to transition between intravenous and oral therapy, but
formulation-dependent differences in oral absorption have historically limited how reliably that transition can be made.
Feralconazole (FRZ-104) is a novel broad-spectrum triazole developed as a cyclodextrin-solubilized intravenous solution and an
amorphous solid dispersion oral capsule.
Objective: To characterize and compare the single-dose pharmacokinetics of intravenous and oral feralconazole in healthy
volunteers, including absolute oral bioavailability, plasma protein binding, and food effect, and to interpret these findings against
published pharmacokinetic data for isavuconazole, posaconazole, voriconazole, and the echinocandins.
Methods: Twenty-four healthy adults received a single 200 mg intravenous infusion and a single 300 mg oral capsule dose of
feralconazole in a randomized, two-period crossover design with a 21-day washout; a 12-subject sub-study assessed food effect.
Plasma concentrations were quantified by validated LC-MS/MS, and non-compartmental pharmacokinetic analysis was
performed.
Results: Intravenous dosing produced a mean Cmax of 5.14 μg/mL and AUC0-∞ of 182.4 μg·h/mL; oral dosing produced a mean
Cmax of 1.87 μg/mL at a median Tmax of 4.0 hours and AUC0-∞ of 176.1 μg·h/mL, corresponding to an absolute bioavailability of
64.6% (90% CI 58.2-71.7%). Terminal half-life was similar between routes (56.3 vs 61.4 hours), a high-fat meal increased oral
AUC0-∞ by only 14%, and plasma protein binding was high and concentration-independent at 98.6% for both formulations.
Conclusion: Feralconazole's oral capsule achieves moderate, food-tolerant, route-independent absorption that falls short of
isavuconazole's near-complete bioavailability but compares favorably with older triazole oral formulations and represents a
workable basis for IV-to-oral switch therapy, pending pharmacokinetic evaluation in the immunocompromised and
hypoalbuminemic populations who are the intended recipients of this drug.
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