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
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".