Abstract: SA-PO0248
Nonequilibrium Voclosporin Disposition Following IV and Oral (PO) Administration: Tissue Levels in Kidney, Liver, Pancreas, and Heart Distinct from Plasma Drug Levels and Dependent on Route of Administration
Session Information
- Pharmacology
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Zhou, Simon, Aurinia Pharmaceuticals Inc, Edmonton, Alberta, Canada
- Duan, Shengnan, University of Michigan, Ann Arbor, Michigan, United States
- Wen, Bo, University of Michigan, Ann Arbor, Michigan, United States
- Im, Seol Hee, iCura Diagnostics, Inc., Malvern, Pennsylvania, United States
- Davis, Kathleen O'Rourke, iCura Diagnostics, Inc., Malvern, Pennsylvania, United States
- Rehaume, Linda M., Aurinia Pharmaceuticals Inc, Edmonton, Alberta, Canada
- Song, Buer, iCura Diagnostics, Inc., Malvern, Pennsylvania, United States
- Sun, Duxin, University of Michigan, Ann Arbor, Michigan, United States
Background
Voclosporin (VCS) is approved for the treatment of adults with active lupus nephritis (LN). In this study, we assess VCS oral bioavailability and corresponding drug levels in mice kidney, liver, pancreas and heart tissues.
Methods
A single dose of 2.5 mg/kg VCS was administered IV or PO in mice (n=3/group). Plasma was collected at 0.5, 1, 2, 4, 7, 12 and 24 hrs, and kidney, liver, pancreas and heart tissues were collected at 0.5, 4, and 12 hrs. Samples were homogenized, and VCS was quantified in plasma and tissue samples by LC-MS. Multiplex fluorescent imaging was used to detect VCS within tissues.
Results
VCS IV clearance was ~30 mL/mL/kg and absolute oral bioavailability was 4.3% in mice. IV and PO administration of VCS yielded higher tissue concentrations than plasma suggesting rapid distribution into tissues. The ratios of VCS in liver vs. plasma following PO administration at 8 and 24 hrs were 46.1 and 136.4 as compared to 28.9 and 27.2 at 8 and 24 hrs following IV administration. In contrast, the ratios of VCS following IV administration in kidney, pancreas and heart vs plasma at 8 hrs were significantly higher than the respective ratios at 8 hrs following PO administration. Kidney imaging showed rapid elimination of VCS from cortex to medulla following both IV and PO administration. There was no VCS retention in podocytes or proximal tubules. While the LC-MS detected higher VCS in kidney at 24 hrs with IV than PO, there appeared no difference in the imaging of VCS from cortex to medulla, likely by higher VCS in urine following IV administration.
Conclusion
With rapid hepatic clearance and poor oral absorption, the absolute oral bioavailability of VCS is less than 5% in mice. VCS rapidly distributes into tissues of liver, kidney, pancreas and heart. Compared to IV administration, oral administration was associated with lower plasma concentrations with significantly higher hepatic uptake/retention and lower pancreatic and cardiac uptake/retention. Consistent with non-equilibrium disposition dependent on route of administration and blood flow, VCS demonstrates distinct tissue distribution not directly correlated with plasma drug levels.
Funding
- Commercial Support – Aurinia Pharmaceuticals Inc.