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Abstract: PO2369

Impact of Renal Impairment and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat

Session Information

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

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

Authors

  • Groenendaal-van de Meent, Dorien, Astellas Pharma Europe B.V., Leiden, Netherlands
  • Kerbusch, Virginie, PharmAspire, Wijchen, Netherlands
  • Kaspera, Rudiger, Astellas Pharma Europe B.V., Leiden, Netherlands
  • Barroso, Maria Begona, Astellas Pharma Europe B.V., Leiden, Netherlands
  • Galletti, Piergiorgio, Astellas Pharma Europe B.V., Leiden, Netherlands
  • Klein, Gernot, APEX GmbH, Munich, Germany
  • den Adel, Martin, Astellas Pharma Europe B.V., Leiden, Netherlands
Background

Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of CKD anemia. The objective was to evaluate the pharmacokinetics (PK), metabolic profile, pharmacodynamics, and safety of roxadustat in patients (pts) with varying degrees of renal function (RF).

Methods

In this phase 1, open-label study (EudraCT: 2015-002565-28), pts were enrolled in one of four RF groups: normal (NRF; eGFR ≥90 mL/min/1.73 m2); severely impaired (SIRF, not on dialysis; eGFR <30 mL/min/1.73 m2); end-stage renal disease (ESRD) on continuous ambulatory or automated peritoneal dialysis (CAPD/APD); or ESRD on hemodialysis or hemodiafiltration (HD/HDF). Patients in the NRF, SIRF, and CAPD/APD groups received a single dose of 100-mg oral roxadustat on Day 1. Two treatment periods (P1/P2), separated by a washout period, were used for HD/HDF pts; a single dose of 100-mg oral roxadustat occurred 2 hours after HD/HDF (P1) and 2 hours before HD/HDF, 2 days after the previous session (P2). The PK of roxadustat and its circulating metabolites (O-glucuronide-, O-glucoside-, and sulphate of hydroxy-roxadustat) were evaluated.

Results

Thirty-four pts were enrolled and received roxadustat (NRF, n=12; SIRF, n=9; CAPD/APD, n=1; HD/HDF, n=12). The geometric least-square mean ratio of AUCinf relative to NRF pts was 223% (90% CI: 185, 268) and 195% (90% CI: 165, 229) in SIRF and HD/HDF, respectively. Roxadustat’s Cmax and t1/2 were comparable between groups. The PK of roxadustat and its metabolites were not affected by HD/HDF. In NRF, the amount of unchanged roxadustat excreted in urine was <1%; urinary excretion and renal clearance of roxadustat and its metabolites decreased with lower baseline RF. Mean AUCinf and t1/2 for roxadustat’s circulating metabolites were higher in SIRF and HD/HDF pts, compared to NRF. Metabolite:parent ratio of AUCinf was <1% for O-glucuronide- and O-glucoside-roxadustat, and <10% for sulphate of hydroxy-roxadustat. Roxadustat was well tolerated in all groups.

Conclusion

The AUC for roxadustat and its metabolites was higher in SIRF and HD/HDF, compared to NRF. Roxadustat’s Cmax and t1/2 were comparable among all groups. Roxadustat and its metabolites were not significantly cleared by HD/HDF.

Funding

  • Commercial Support