Objective:

To determine the pharmacokinetic profile of VCS in subjects with hepatic impairment after single or multiple doses.

Methods:

VCS 0.4 mg/kg was administered to subjects with hepatic function defined by Child-Pugh classes A (mild impairment) and B (moderate impairment) and matched healthy volunteers (normal hepatic function).Subjects with moderate impairment received only a single 0.4 mg/kg VCS dose on Day 1. Blood and urine samples were collected for 48 and 24 hours, respectively, and analyzed for VCS concentrations and selected VCS metabolites.

Results:

Day 1

Mean VCS concentrations were increased in subjects with mild and moderate hepatic impairment with corresponding increases in Cmax and AUC(0 48). Geometric least squares mean ratios, mild-to-normal and moderate-to-normal, were 145% for both groups for Cmax, and 167% and 196% for AUC(0-48), respectively. In both groups, the 90% confidence intervals for both Cmax and AUC(0-48) exceeded the upper 80% to 125% equivalence bound.

Day 10

Mean VCS concentrations were increased in subjects with mild hepatic impairment with corresponding increases in Cmax and AUC(0 48). Geometric least squares mean ratios, mild-to-normal, was 148% and 179%, for Cmax and AUC(0-12), respectively, and the 90% confidence interval for both Cmax and AUC(0-12) exceeded the 80% to 125% equivalence bound. An inspection of Cmax and AUC scatter plots demonstrated that there was some overlap in the range of values for both parameters, however, a trend was observable indicating increased exposure among subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function.

Exposure to VCS metabolites was 2 to 6-fold higher in the 2 hepatically impaired groups than in the normal hepatic function group. The urinary excretion amount and rate of voclosporin and each of the metabolites increased with increasing impairment of hepatic function.

Conclusions:

Administration of voclosporin to subjects with mild to moderate hepatic impairment significantly increased exposure to voclosporin. These data demonstrate that VCS should be administered with appropriate concentration and safety monitoring for patients with mild to moderate hepatic impairment.

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

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