Oral Hypoxia‐Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG‐4592) for Treatment of Anemia in Chronic Kidney Disease: A Placebo‐Controlled Study of Pharmacokinetic and Pharmacodynamic Profiles in Hemodialysis Patients

Abstract

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before dialysis on day 8. Maximum plasma concentration and area under the plasma concentration-time curve for patients receiving roxadustat were slightly more than dose proportional and elimination half-life ranged from 14.7 to 19.4 hours. Roxadustat was highly protein bound (99%) in plasma, and dialysis contributed a small fraction of the total clearance: only 4.56% and 3.04% of roxadustat recovered from the 1 and 2 mg/kg dose groups, respectively. Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1-and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment-or dose-related trends in adverse event incidence.

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

“…The pharmacokinetics of roxadustat after oral administration are well characterized (Table 1 ) and appear to be linear (Yu [ 71 ], Groenendaal [ 26 , 27 ], Groenendaal [ 28 ], Shibata [ 62 ], Shibata [ 63 ], Provenzano [ 55 ], Rekic [ 59 ], Groenendaal [ 29 , 30 ], Takada [ 67 ]). Roxadustat is readily absorbed after oral administration, has a moderate apparent volume of distribution, and is eliminated largely by metabolism (cytochrome P450 (CYP) 2C8, UDP-glucuronosyltransferase (UGT) 1A9).…”

The efficacy of Roxadustat for the treatment of anemia in dialysis dependent chronic kidney disease patients: an updated systematic review and meta-analysis of randomized clinical trials

“…ROX binds to plasma protein, mainly albumin, and the fraction unbound is about 1.2% in DD-CKD (12). ROX is mainly removed from the body by phase I oxidation (CYP2C8) and phase II conjugation (glucuronidation and glucosidation); thus, dialysis accounts for a small portion of the ROX elimination (12,13). Few RCTs studied the effect of ROX compared to ESA on DD-CKD patients, but there were conflicting results regarding the efficacy and safety of ROX on DD-CKP patients.…”

Whether Prolyl Hydroxylase Blocker—Roxadustat—In the Treatment of Anemia in Patients with Chronic Kidney Disease Is the Future?

“…The studies, which compared the effects of roxadustat to those of placebo [ 22 , 23 , 24 , 25 , 26 , 29 ] demonstrated a significant increase in hemoglobin concentrations after roxadustat, both in conservatively treated and dialyzed patients.…”

“…The studies which juxtaposed the effects of roxadustat with those of erythropoietin [ 22 , 25 , 27 , 29 , 30 ] or darbapoietin [ 28 ], showed that, regarding changes in hemoglobin levels, the effects of roxadustat were not worse, while being usually better than the effects of erythropoietin…”

“…Phase 3 clinical studies of roxadustat were started in 2014. There are currently more than 15 phase 3 clinical trials underway with a target enrollment of about 10,000 patients worldwide, studying the safety, efficacy, and long-term effects of roxadustat in CKD patients, including non-dialysis-dependent [ 23 , 24 , 25 , 26 ], hemodialysis-dependent [ 22 , 25 , 27 , 28 , 29 ] and peritoneal dialysis-dependent subjects [ 25 , 30 ]. See below for a few presented examples.…”