Voclosporin Distribution and Clearance from the Kidneys and Cellular Location Following Coadministration with Ketoconazole or Rifampin

Background: In drug-drug interaction studies in healthy humans, administration of voclosporin (VCS) with 600 mg QD of rifampin (RIF; cytochrome P450 [CYP] 3A4 inducer) or 400 mg QD ketoconazole (KCZ; CYP3A4 inhibitor) produced significant reduction and increase of whole blood AUC by 87% and 1800%, respectively. In this study, these CYP-based interactions were assessed in murine plasma and kidney tissue. Methods: VCS 2.5 mg/kg was administered IV or PO to mice alone or after 4 days of KCZ (60 mg/kg PO) or RIF (10 mg/kg PO) pretreatment (n=3 mice/group). Plasma was collected at 0.5, 1, 2, 4, 7, 12 and 24 hrs, and kidneys were collected at 0.5, 4, and 12 hrs. VCS, KCZ and RIF were quantified in plasma and kidney samples by LC-MS. Multiplex fluorescent imaging detected VCS within kidney samples in podocytes, proximal tubule cells, loop of Henle/ early distal tubule cells, endothelial cells, macrophages, and T cells. Results: VCS IV and PO yielded higher kidney tissue concentrations than plasma. IV VCS with KCZ slightly increased VCS plasma concentrations, whereas IV VCS with RIF had no effect. Both KCZ and RIF increased plasma VCS concentrations following PO VCS. Imaging IV VCS in kidney showed rapid elimination in kidney from cortex to medulla; KCZ and RIF yielded higher VCS retention from cortex to medulla cells compared to VCS alone. PO VCS showed delayed kinetics in the kidney with a stronger exposure signal at later timepoints. Although VCS blood clearance was altered by KCZ and RIF, VCS exposure in kidney was elevated. There was no evidence of drug retention in podocytes with IV or PO VCS in presence of KCZ or RIF, whereas VCS was detected in proximal tubules, loop of Henle/ early distal tubules, and blood vessels. Conclusion: Upon IV and PO administration, VCS rapidly distributes into the kidney. As VCS demonstrates non-equilibrium disposition following IV and PO administration, drug interaction with KCZ or RIF elevated VCS kidney exposure differentiated from the altered VCS plasma exposure. VCS is rapidly cleared from the kidney and although its retention is modified with CYP inhibition or induction, VCS does not accumulate within the glomeruli or podocytes, with transient flow observed through the cortex, medulla and pelvic regions. Funding: Commercial Support - Aurinia Pharmaceuticals Inc.

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