Objective:

To assess the effects of fasting, consumption of a high-fat breakfast and consumption of a low-fat breakfast on the absorption of VCS, a new calcineurin inhibitor (CNi), from an oral solution after administration to healthy volunteers.

Methods:

This was a Phase 1, single center, randomized, single-dose, open-label, 3-treatment crossover food interaction study. A single 1.5 mg/kg dose of VCS was administered after an overnight fast, after consumption of a low fat breakfast, and after consumption of a high fat breakfast. Whole blood concentrations were determined for 72 hours after dosing and analyzed using an isomer specific validated LC/MS-MS assay method. A significant food effect was to be concluded if the 90% geometric confidence intervals of the ratios (high-fat/fasted and low-fat/fasted) of least-squares means from the ANOVA of the ln-transformed AUC0-t and AUC0-inf were within 80% to 125% and within 70% to 143% for ln-transformed Cmax.

Results:

Administration of voclosporin with either a low fat or high fat breakfast resulted in a decrease in mean Cmax voclosporin (trans isomer) whole blood concentrations, (789.43±269.25 ng/mL vs. 562.52±207.95 ng/mL vs. 385.03±202.16 ng/mL, for fasted, low-fat and high-fat treatments, respectively). Systemic exposure as measured by AUC(inf) also decreased (4054.15±1774.03 ng.h/mL vs. 3458.47±1786.51 ng.h/mL vs. 3103.43±1745.50 ng.h/mL, for fasted, low-fat and high-fat treatments respectively). The geometric least squares mean ratios ranged from 71.44% to 85.04%, low fat-to-fasted, and 47.47% to 75.09%, high fat-to-fasted and the lower limits of all confidence intervals were < 70.0% for Cmax and < 80.0% for AUCinf, indicating a significant effect of food on the extent of absorption. The mean Tmax increased from 1.77 h under fasted conditions to 1.90 h and 2.32 h with a low and high fast breakfast, respectively. Combined with the decrease in Cmax, this indicates a decrease in the apparent rate of absorption as well.

Conclusions:

Oral administration of voclosporin with either a low or high fat breakfast results in a significant decrease in the rate and extent of absorption which appears to be related to the fat content of the meal. This decrease in exposure can be clinically significant in renal transplantation, and therefore VCS should be administered on an empty stomach to ensure adequate exposure and efficacy.

Aspeslet, L.: Employee, Isotechnika. Freitag, D.: Employee, Isotechnika. Huizinga, R.: Employee, Isotechnika. Ling, S.: Employee, Isotechnika. Mayo, P.: Employee, Isotechnika. Foster, R.: Employee, Isotechnika.

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