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Abstract: PO2368

Pharmacokinetic Evaluation of Drug Interactions Between Vadadustat and HMG-CoA Reductase Inhibitors (Statins)

Session Information

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

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

Authors

  • Chavan, Ajit B., Akebia Therapeutics Inc, Cambridge, Massachusetts, United States
  • Sawant, Rishikesh, Akebia Therapeutics Inc, Cambridge, Massachusetts, United States
  • Burke, Leontia, AGTC, Cambridge, Massachusetts, United States
  • Paulson, Susan K., Akebia Therapeutics Inc, Cambridge, Massachusetts, United States
Background

Cardiovascular disease is the most common cause of mortality in patients with chronic kidney disease (CKD). Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) in late-stage development for the treatment of anemia due to CKD. The prevalence of dyslipidemia in CKD is very high, and nearly 50% of patients have been prescribed statins to decrease cholesterol levels. The disposition of most statins is dependent on metabolic enzymes and transporters. This study evaluated the drug interaction potential for statins when co-administered with vadadustat.

Methods

In this 3-part study (NCT03801733), 108 healthy adults were enrolled for vadadustat-statin pharmacokinetic (PK) evaluation. Vadadustat (600 mg daily) was administered concomitantly with either rosuvastatin (20 mg; n=34), pravastatin (40 mg; n=26), atorvastatin (40 mg; n=24), or simvastatin (40 mg; n=24). PK evaluation of the statins was conducted following a single dose on Day 1 and after the washout period of a single dose when co-administered with steady state vadadustat. After treatment with a statin alone or a statin plus vadadustat, geometric mean ratios were calculated to determine the difference in the PK parameters area under the curve (AUC) and maximum concentration (Cmax).

Results

Vadadustat was generally well tolerated by healthy subjects when taken alone or with statins. Exposure (AUC and Cmax) to rosuvastatin, a BCRP and OATP1B1 substrate, increased 2- to 3-fold in the presence of vadadustat. No change in exposure to pravastatin (an OATP1B1 substrate) was observed. The AUC for atorvastatin (a BCRP and OATP1B1 substrate) increased 1.4-fold, although no change in Cmax was noted; for simvastatin (a BCRP and OATP1B1 substrate), the AUC increased 2-fold and Cmax increased 1.2-fold in the presence of vadadustat.

Conclusion

There were no clinically significant interactions with pravastatin or atorvastatin, suggesting that vadadustat has a low likelihood for OATP1B1-mediated drug interactions. Increases in exposures to rosuvastatin and simvastatin are possibly due to BCRP inhibition. In summary, these results provide information to aid in the management of concomitant administration of vadadustat with statins.

Funded by: Akebia Therapeutics, Inc.

Funding

  • Commercial Support – Akebia Therapeutics