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Abstract: PO2375

Clinical Pharmacology of Apixaban in Nephrotic Syndrome

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Derebail, Vimal K., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Zhu, Jing, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Martin, Karlyn A., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Grant, Russell P., Laboratory Corporation of America, Burlington, North Carolina, United States
  • Patel, Sheel M., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Maffuid, Kaitlyn, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Froment, Anne B., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Torrice, Chad, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Key, Nigel S., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Crona, Dan, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Background

Nephrotic syndrome (NS) confers high venous thromboembolism (VTE) risk, but no standard-of-care exists for thromboprophylaxis. Apixaban, an oral direct Factor Xa inhibitor, has favorable renal clearance but is highly protein bound and has not been studied in NS. We evaluated safety, pharmacokinetics (PK) and pharmacodynamics (PD) in NS subjects in a parallel-arm single-dose (apixaban 10mg) Phase 1 study.

Methods

NS subjects were included if: age 18-79 years; urine protein:creatinine >3.5 g/g or serum albumin <3.0 g/dL; non-diabetic NS. Blood was collected at 0, 0.5, 1, 3, 4, 6, 8, 24h for PK (total and free apixaban, anti-Xa levels) and at 0, 3, 6 and 24h for thrombin generation. Apixaban was quantified by liquid chromatography-tandem mass spectrometry, anti-Xa levels by a chromogenic assay, thrombin generation by a fluorescence assay, and D-dimer by ELISA. Non-compartmental analyses for PK utilized Phoenix 8.1, and linear regression models tested associations between PK and PD (SAS JMP 14.0).

Results

8 NS and 11 healthy subjects completed the study. NS subjects had mean UPC ratio of 6.7 g/g and were older (mean age 28.0 v 42.7 years, P=0.01); other relevant baseline characteristics were similar. Anti-Xa levels and PK measures (Cmax, Tmax, AUC0-24, Vd/F, t1/2 and CL/F) for total (Figure) and free apixaban were similar between NS and healthy subjects. D-dimer was lower in healthy subjects at 24h (P=0.04). Peak thrombin generation did not differ over 24h. Correlations between free apixaban and peak thrombin generation at 3h were seen in healthy subjects (r2=0.48, P=0.02 for Cmax; r2=0.38, P=0.04 for AUC0-24) but not in NS. No adverse events occurred.

Conclusion

These preliminary data support prospective study of apixaban for thromboprophylaxis in NS. Additional multi-dose data will inform appropriate dosing for patients with proteinuria due to NS.

Total apixaban concentration over time in NS and healthy subjects

Funding

  • Other NIH Support