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

Abstract

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 (C max ) and area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUC inf ) 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 C max and AUC inf 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 C max and AUC inf were statin and administration time dependent. When coadministered with roxadustat, statin-associated adverse reactions and the need for statin dose reduction should be evaluated.

Pharmacokinetics and Bioequivalence of Two Formulations of Rosuvastatin Following Single‐dose Administration in Healthy Chinese Subjects Under Fasted and Fed Conditions

“…The study results showed that the mean C max , AUC 0-t , and AUC 0-∞ after single-dose administration of rosuvastatin 10 mg under fasted conditions were 4.94 ng/mL, 67.61 h•ng/mL, and 61.46 h•ng/mL, respectively. 23 These values were notably lower than the corresponding values in our study, suggesting that the systemic exposure of rosuvastatin was increased in Chinese populations compared to Caucasian populations, and this is consistent with the conclusion of a previous study. 10 Moreover, the above clinical study considered two treatment-emergent AEs observed in two (7.1%) subjects after administration of rosuvastatin.…”

“…A clinical study involving the pharmacokinetics of rosuvastatin 10 mg was performed in Caucasian subjects. The study results showed that the mean C max , AUC 0–t , and AUC 0–∞ after single‐dose administration of rosuvastatin 10 mg under fasted conditions were 4.94 ng/mL, 67.61 h·ng/mL, and 61.46 h·ng/mL, respectively 23 . These values were notably lower than the corresponding values in our study, suggesting that the systemic exposure of rosuvastatin was increased in Chinese populations compared to Caucasian populations, and this is consistent with the conclusion of a previous study 10 .…”

Roxadustat: Not just for anemia

“…However, phosphorus-lowering drugs, such as calcium acetate and sevelamer, may form insoluble chelates with roxadustat and reduce its absorption ( Groenendaal-van de Meent et al, 2021b ). In addition, roxadustat significantly increases the blood level of statins because it inhibits the pharmacokinetic interaction of organic anion transporting polypeptide 1B1/B3 (OATP1B1/B3) with statins ( Groenendaal-van de Meent et al, 2022 ). Therefore, when statins are co-administered with roxadustat, adverse reactions should be evaluated and the statin dose should be reduced or the interval between the roxadustat doses should be increased.…”

Understanding Statin‐Roxadustat Drug–Drug‐Disease Interaction Using Physiologically‐Based Pharmacokinetic Modeling

“…The dashed lines represent the interval of 0.8 to 1.25 and the shaded area represents the interval between 0.5 and 2. (c) Summary of simulated vs. observed geometric means ratios for statins (ref 20…”

“…Roxadustat has good oral bioavailability and low clearance. Metabolism is mainly mediated by UGT1A9 and CYP2C8 and it is a substrate of BCRP and OATP1B1 transporters 20 . Based on in vitro and clinical studies, roxadustat does not inhibit CYP or UGT enzymes, 21 but is a potential inhibitor of BCRP, OATP1B1/3, and OAT3 transporters 20 .…”