Kidney Week

Abstract: PO2369

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

Session Information

• Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

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

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

Authors

• Groenendaal-van de Meent, Dorien, Astellas Pharma Europe B.V., Leiden, Netherlands

Dorien Groenendaal-van de Meent,

• Kerbusch, Virginie, PharmAspire, Wijchen, Netherlands

Virginie Kerbusch,

• Kaspera, Rudiger, Astellas Pharma Europe B.V., Leiden, Netherlands

Rudiger Kaspera,

• Barroso, Maria Begona, Astellas Pharma Europe B.V., Leiden, Netherlands

Maria Begona Barroso,

• Galletti, Piergiorgio, Astellas Pharma Europe B.V., Leiden, Netherlands

Piergiorgio Galletti,

• Klein, Gernot, APEX GmbH, Munich, Germany

Gernot Klein,

• den Adel, Martin, Astellas Pharma Europe B.V., Leiden, Netherlands

Martin den Adel,

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 AUC_inf relative to NRF pts was 223% (90% CI: 185, 268) and 195% (90% CI: 165, 229) in SIRF and HD/HDF, respectively. Roxadustat’s C_max and t_1/2 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 AUC_inf and t_1/2 for roxadustat’s circulating metabolites were higher in SIRF and HD/HDF pts, compared to NRF. Metabolite:parent ratio of AUC_inf 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 C_max and t_1/2 were comparable among all groups. Roxadustat and its metabolites were not significantly cleared by HD/HDF.

Funding

• Commercial Support – Astellas Pharma, Inc.