Objective:

To determine the pharmacokinetic profile of VCS in subjects with renal impairment.

Methods:

VCS 0.4 mg/kg was administered to subjects with Normal, Mild, Moderate, or Severe renal impairment as defined by estimated creatinine clearance (> 80, ≥ 50, ≥ 30 and <30 mL/min, respectively). Subjects with Severe Impairment received only a single 0.4 mg/kg VCS dose. 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 comparable between Normal, Mild, and Moderate groups with no significant differences in either Cmax or AUC(0 48). Mean VCS concentrations were slightly higher in the Severe group with geometric least squares mean ratios, Severe-to-Normal of 122% and 148%, for Cmax and AUC(0-48), respectively, and 90% confidence intervals for both Cmax and AUC(0-48) above the 80% to 125% equivalence bounds.

Day 10

Mean VCS concentrations were comparable between the Normal and Mild groups with no increases in either Cmax or AUC(0 12), although the 90% confidence interval for Cmax (71.6 – 135.3%) exceeded both the upper and lower bounds of the 80% to 125% equivalence window. In the Moderate impairment group, there was an increase in both Cmax and AUC(0-12) with geometric least squares mean ratios, Moderate-to-Normal of 129% and 123%, respectively, while the 90% confidence interval for both Cmax and AUC(0-12) exceeded the 80% to 125% equivalence bounds. An inspection of Cmax and AUC scatter plots demonstrates considerable overlap between groups suggesting that the wide confidence intervals may be due to the study design and sample size and do not reflect a true difference in exposure in the renally impaired groups. The study demonstrated that the urinary pathway was a minor elimination route for VCS and its metabolites, with less than 0.1% of any the five drug-related compounds accounted for in the 24 hour urine after the dose on Day 1.

Conclusions:

As renal excretion accounts for only 2% of VCS elimination after oral dosing no VCS dose adjustment is required in Mild to Moderate renal impairment. Severe renal impairment may result in an approximately 1.5-fold increase in VCS exposure (AUC) but without any significant increase in peak concentrations after a single dose. These data demonstrate that VCS can be administered safely in patients with mild to moderate renal impairment. Appropriate concentration and safety monitoring is recommended for patients with severe renal impairment.

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

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