Population pharmacokinetic modelling of itraconazole and hydroxyl-itraconazole for oral Lozanoc® and Sporanox® capsule formulations in healthy volunteers in fed and fasted state.

Background: Itraconazole is an orally active broad spectrum anti-fungal agent used for treatment of fungal infections. It has a complex absorption kinetics with high between- and within-individual variability in addition to food effects. Hydroxy-itraconazole is the predominant active metabolite. Lozanoc is a novel Mayne Pharma formulation of oral itraconazole with significantly greater bioavailability than the innovator product Sporanox.

Objectives: To develop a population pharmacokinetic model for itraconazole and hydroxy-itraconazole that can effectively describe single- and multi-dose studies for Lozanoc and Sporanox, with particular emphasis on quantifying the effects of food and formulation on oral absorption, and their implications on itraconazole exposure metrics.

Methods: The oral plasma PK data used in the analysis were pooled Lozanoc and Sporanox concentrations from seven Phase I cross-over design trials conducted by Mayne Pharma international on healthy volunteers. PK data were available for a range of single-dose studies, in both fed and fasted states, and multi-dose studies in the fed state. Overall, there were 244 subjects with a total of 20656 PK observations (an average of 85 observations per subject).
A model of single-dose itraconazole to define food and formulation effects was developed, this was then extended to multi-dose data. Covariate effects were then examined, before extending it to describe hydroxy-itraconazole. Modelling was performed using NONMEM® software.

Results: The final model of itraconazole was a 2-compartment model with oral absorption described by 4-transit compartments. The multi-dose kinetics of itraconazole was described by total effective daily dose- and time-dependent changes in clearance. Lozanoc had a relative bioavailability of 173% compared to Sporanox and was 21% less variable. The fed status influenced the kinetics of itraconazole via two mechanisms; a decrease in the relative bioavailability to 73.1% of the fasted state, and a decrease in transit absorption rate constant (KTR) to 41.7% of the fasted state.
The apparent central clearance (CL/F) and KTR for subjects from UK studies was 83.4% and 133.8%, respectively, compared to subjects from US studies.
Hydroxy-itraconazole data were best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose hydroxy-itraconazole data and a time-dependent clearance for hydroxy-itraconazole multi-dose data.

Conclusions: This analysis presents the most extensive population PK model of itraconazole and hydroxy-itraconazole in the literature. The PK modelling suggests that food decreases itraconazole absorption irrespective of the formulation. The presented model can be used to predict itraconazole exposure using different dosing regimens to ensure optimized therapeutic efficacy.