Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Abstract

Background and Objectives Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. Methods This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUC inf ), maximum concentration ( C max ), and terminal elimination half-life ( t 1/2 ) were assessed for roxadustat; AUC and C max were assessed for erythropoietin. Results Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUC inf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; C max and t 1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUC inf and t 1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and C max of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. Conclusions Kidney function impairment increased the AUC of roxadustat and its metabolites. The C max and t 1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.

Transcription-Based Multidimensional Regulation of Fatty Acid Metabolism by HIF1α in Renal Tubules

“…The dosage adopted should also be important for PHD inhibitor effects. Actually, the effective FG-4592 concentration in anemia treatment was much lower than that in our experiment (Groenendaal-van de Meent et al, 2021).…”

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

“…When roxadustat concentrations decrease, the EPO levels decline faster here in animals than in humans [16]. EPO erythropoetin, t max time to reach maximum concentration, C max maximum concentration, AUC area under the concentration-time curve, t peak time to peak concentration, AUEC area under the effect-time curve response of endogenous EPO lasts for 24 h, contrasting to 48 h in dialysis-dependent patients [29,56].…”

“…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).…”

“…Elimination of unchanged roxadustat in urine was only 1.3% (1.0–1.6) of the orally administered dose (Table 1 ),correspondingly, renal clearance (CL ren ) was low at 0.028 L/h (0.03–0.026). In volunteers with normal renal function, 20.3% of an oral dose was recovered in urine as O-glucuronide-roxadustat, 7.21% was recovered as O-glucoside-roxadustat, and 2% was recovered as sulphate of hydroxy-roxadustat [ 29 ].…”

“…This compares to a much faster roxadustat absorption t ½ of 0.74 or 1.1 h based on the reported absorption rate constants of 0.94 or 0.63 per hour [ 59 , 67 ]. The area under the EPO concentration-time curve adds up to 1390 h·IU/L [ 29 ]. Because the EPO kinetics are induced by roxadustat, the kinetic parameters can be interpreted as pharmacodynamic parameters of the roxadustat effect on EPO (Table 2 ).…”