Evaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects

Abstract

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94. 44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions. Keywords drug-drug interaction, food-drug interaction, pharmacokinetics, roxadustat, spherical carbon adsorbent Chronic kidney disease (CKD) is a condition characterized by long-term decline in renal function that typically requires dialysis treatment in later stages and is often associated with other comorbidities such as hypertension, diabetes, and cardiovascular disease. 1,2Anemia is a complication that often accompanies CKD, and is characterized by reduced hemoglobin levels, resulting, in part, from the inability of the failing kidneys to produce sufficient erythropoietin. The incidence of anemia among subjects with CKD increases with the severity of disease 3 and is associated with an impaired quality of life. Roxadustat (ASP1517, FG-4592, AZD9941) is an orally active, hypoxia-inducible factor prolyl hydroxylase inhibitor 5 that promotes erythropoiesis by increasing endogenous erythropoietin. Roxadustat has demonstrated safety and efficacy in phase 2 studies by increasing hemoglobin levels in subjects with 1 Clinical Pharmacology, Development, Astellas Pharma Inc., Tokyo, Japan 2 Research Program Management, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan 3 Clinical ...

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

“…Following a single oral dose of roxadustat at 0.3, 1, 2, 3 or 4 mg/kg, the mean maximal concentrations of roxadustat were previously reported to be 1, 5, 11, 17 and 26 μg/mL (i.e., 2.8, 14.2, 31.2, 48.2 or 73.8 μM), respectively [1,52,53]. In this study, the IC 50 values required for roxadustat-mediated inhibition of peak or late I K(DR) in GH 3 cells were estimated to be 5.71 or 1.32 μM, respectively.…”

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

“…Daprodustat showed potential DDI with weak inhibitor of 2C8 (trimethoprim) and a strong inhibitor of 2C8/OATP1B1 (gemfibrozil) [44,45]. Desidustat is less likely to show clinically relevant CYP enzyme and transporter mediated DDI as compared to other HIF-PHI [42,44].…”

“…The transporter interaction study revealed no or minimal potential for interaction with hepatic uptake transporters OATP1B1/OATP1B3 (data on file). In contrast, Roxadustat is primarily metabolized via CYP2C8 [42], which might leads to potential drug-drug interaction (DDI) with potent inhibitor of CYP2C8 (gemfibrozil). The coadministration of roxadustat and statins showed increase in systemic drug exposure of statins, warranted for dose adjustment at high doses [43].…”

Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non‐elderly healthy adult male subjects

“…These drug‐drug interactions may be due to formation of chelate complexes between lanthanum cations and concomitant drugs, resulting in reduced bioavailability. A similar drug‐drug interaction study evaluated the pharmacokinetics of roxadustat when administered concomitantly with spherical carbon adsorbent and with or without food and reported that both conditions did not have a clinically relevant impact on the absorption of roxadustat . Given that the potential interaction between roxadustat and lanthanum carbonate in this study would occur in the gastrointestinal tract and in turn impact the absorption of roxadustat, it is not anticipated that any major differences in drug‐drug interaction would be observed between healthy subjects and those with CKD.…”

“…A similar drug-drug interaction study evaluated the pharmacokinetics of roxadustat when administered concomitantly with spherical carbon adsorbent and with or without food and reported that both conditions did not have a clinically relevant impact on the absorption of roxadustat. 17 Given that the potential interaction between roxadustat and lanthanum carbonate in this study would occur in the gastrointestinal tract and in turn impact the absorption of roxadustat, it is not anticipated that any major differences in drug-drug interaction would be observed between healthy subjects and those with CKD. Overall, we found the AUC inf and C max of roxadustat to be 12% and 1.42% lower, respectively, when administered concomitantly with lanthanum carbonate; however, the GMRs for AUC inf and C max were 88.00% (90% CI: 84.01-92.17) and 98.58% (90% CI: 92.92-104.58), respectively, and the 90% CIs were within the no-effect boundaries of 80% and 125%.…”