Effect of Roxadustat on the Pharmacokinetics of Simvastatin, Rosuvastatin, and Atorvastatin in Healthy Subjects: Results from 3 Phase 1, Open-Label, 1-Sequence, Crossover Studies.

Roxadustat inhibits breast cancer resistance protein and organic anion transporting polypeptide 1B1, which can affect coadministered statin concentrations. Three open-label, 1-sequence crossover phase 1 studies in healthy subjects were conducted to assess effects from steady-state 200-mg roxadustat on pharmacokinetics and tolerability of 40-mg simvastatin (CL-0537 and CL-0541), 40-mg atorvastatin (CL-0538), or 10-mg rosuvastatin (CL-0537). Statins were dosed concomitantly with roxadustat in 28 (CL-0537) and 24 (CL-0538) healthy subjects, resulting in increases of maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ) 1.87- and 1.75-fold for simvastatin, 2.76- and 1.85-fold for simvastatin acid, 4.47- and 2.93-fold for rosuvastatin, and 1.34- and 1.96-fold for atorvastatin, respectively. Additionally, simvastatin dosed 2 hours before, and 4 and 10 hours after roxadustat in 28 (CL-0541) healthy subjects, resulted in increases of Cmax and AUCinf 2.32- to 3.10-fold and 1.56- to 1.74-fold for simvastatin and 2.34- to 5.98-fold and 1.89- to 3.42-fold for simvastatin acid, respectively. These increases were not attenuated by time-separated statin dosing. No clinically relevant differences were observed for terminal elimination half-life. Concomitant 200-mg roxadustat and a statin was generally well tolerated during the study period. Roxadustat effects on statin Cmax and AUCinf were statin and administration time dependent. When coadministered with roxadustat, statin-associated adverse reactions and the need for statin dose reduction should be evaluated.