Abstract: PO2021
Chronic Dosing of Voclosporin at Clinically Relevant Exposure Levels Does Not Induce Renal Fibrosis Markers in Rats
Session Information
- Clinical Pharmacology, Pharmacokinetics, and Drug Toxicity in Kidney Diseases
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Rehaume, Linda M., Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
- Collins, Teresa D., Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
- Cross, Jennifer, Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
- Huizinga, Robert B., Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
Background
Although prognosis of lupus nephritis (LN) has improved, the long-term outcome is still poor, with many patients progressing to end-stage renal disease. Calcineurin inhibitors (CNIs) like cyclosporine A (CsA) and tacrolimus have demonstrated benefit in LN; however, prolonged use is associated with renal fibrosis. CsA-induced fibrosis has largely been in the context of high doses required for immunosuppression in transplant patients. Voclosporin (VCS), a potent, novel CNI with a predictable PK/PD profile, is approved for treatment of LN. This study tested the hypothesis that the clinically effective dose of VCS used in LN patients, would not induce fibrosis markers in the chronic dosing rat model compared to CsA and vehicle controls.
Methods
Sprague Dawley rats (n=10/ group) on a low sodium (0.05%) diet were treated by oral gavage (QD) with VCS (4 mg/kg), cyclosporine A control (10 mg/kg) or vehicle control (5 mL/kg) for 3 or 6 weeks. Clinical chemistry was performed on serum and overnight urine. Gene expression (RT-qPCR) and histology were performed on kidneys. Data were analyzed as change from baseline.
Results
There were no significant differences in clinical measures of renal or liver function. There were no significant changes in urine protein/creatinine or fractional excretion. Serum total bilirubin and cholesterol were significantly increased in the CsA treated group compared to vehicle and VCS. At 3 weeks, there was a significant decrease in expression of Tgfb1 and the epithelial-mesenchymal transition (EMT) marker Cdh2 (N-cadherin) in VCS treated animals compared to vehicle and CsA, and significant decreases in expression of the EMT regulators, Snai1 (SNAIL) and Snai2 (SLUG), and the extracellular matrix components (ECM) Col1a1, Col3a1 and Vim in the VCS treated group. At 6 weeks, trends between groups remained, and there were significant decreases in Tgfb2 and Col3a1 in the VCS treated group. At 6 weeks, there were no differences in renal histopathology.
Conclusion
This study shows that the clinically relevant dose of voclosporin does not induce renal fibrosis markers in rats, in contrast to the CsA control. Additionally, voclosporin may protect against renal EMT and ECM deposition, which are associated with CsA. Collection of data from a two-year continuation renal biopsy sub-study of AURORA-1 is ongoing.
Funding
- Commercial Support –