A Mass Balance Study of ¹⁴C‐Labeled JTZ‐951 (Enarodustat), a Novel Orally Available Erythropoiesis‐Stimulating Agent, in Patients With End‐Stage Renal Disease on Hemodialysis

Abstract

The mass balance, pharmacokinetics, and biotransformation of JTZ-951 (enarodustat), a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, were characterized in patients (N = 6) with end-stage renal disease on hemodialysis. Following a 10-mg (100 µCi) oral dose of 14 C-JTZ-951, whole blood, feces, dialysate, and, if feasible, urine were obtained for pharmacokinetic assessments and for metabolite profiling and identification in appropriate matrices. Fecal excretion was the major route of elimination of radioactivity, and urinary excretion a minor route, with mean (coefficient of variation [%CV]) recovery of 77.1 (16.2)% and 10.9 (92.0)% of the dose, respectively. Radioactivity was not detected in the dialysate, and mean (%CV) total recovery in excreta was 88.0 (14.9)%. For parent JTZ-951 in plasma, the mean (%CV) effective half-life was 8.96 (7.7)% hours, and area under the curve over 24 hours comprised the majority (>80%) of total exposure, with relatively low variability in these pharmacokinetic variables. Based on profiling of plasma radioactivity, parent JTZ-951 was the predominant circulating component, accounting for 93.7% or more of radioactivity, and metabolite M2 (hydroxylated product) was the only detectable metabolite, but its exposure was minor (<5%) versus unchanged JTZ-951. In urine and feces, the predominant analyte was JTZ-951, and metabolite M2 was the predominant albeit minor metabolite, with small amounts of other metabolites. Thus, plasma exposure to drug-derived radioactivity was primarily due to parent JTZ-951, and the drug was cleared mainly by excretion of unchanged JTZ-951. The study appropriately characterized the disposition of JTZ-951 in patients with end-stage renal disease.

Hemodialysis Clearance of Enarodustat (JTZ‐951), an Oral Erythropoiesis Stimulating Agent, in Patients with End‐Stage Renal Disease

“…The A‐V difference method is subject to error due to inappropriate use of plasma flow measurements, 14 hemodialysis‐related effects on drug metabolism, 20 and hemodynamic changes (eg, reduction of cardiac output, alteration in peripheral resistance) that result during hemodialysis 18,21 . Whereas the association of enarodustat with red blood cells is low, 13 and dialyzer blood flow was measured in the current study, estimation of dialysis clearance by the A‐V difference method (to compare with the dialysis recovery results) was not possible due to similar pre‐ and postdialyzer concentrations (Figure 3) that precluded estimation of the extraction ratio (ie, [A‐V]/A). Regarding aspects related to the metabolic disposition of enarodustat, the parent drug was the predominant circulating component with minor exposure (<5% vs parent) to metabolite (R)‐M2 (a hydroxlated product), and the drug was cleared mainly by excretion of unchanged enarodustat 13 .…”

“…In a metabolic disposition study with 14 C‐enarodustat in patients with ESRD on hemodialysis, plasma exposure to drug‐derived radioactivity was primarily due to parent enarodustat, with minor exposure to metabolite (R)‐M2 (a hydroxylated product). Enarodustat was cleared from the body mainly by excretion of unchanged drug primarily in feces in patients with ESRD 13 …”

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

“…HIF-PHIs in current clinical development are potent reversible inhibitors of all 3 PHD isoforms, with in vitro halfmaximal inhibitory concentrations in the submicromolar to low micromolar range (Table 1 [68][69][70][71][72][73][74][75][76] ). 68,70,71 HIF-PHIs chelate at the catalytic-site iron, stabilizing both HIF-1a and HIF-2a and resulting in dose-dependent increases in HIF-regulated gene expression.…”

“…The pharmacokinetic parameters for single-dose HIF-PHIs, which are rapidly absorbed after oral administration, are summarized in Table 1. [69][70][71][72][73]75,76 Roxadustat and daprodustat are primarily oxidized by cytochrome P450 (CYP) 2C8, with a c l i n i c a l i n v e s t i g a t i o n VH Haase: HIF-PH inhibitors for anemia of CKD minor contribution of CYP3A4 to daprodustat metabolism. 81,82 In addition to CYP2C8-mediated oxidation, roxadustat undergoes phase 2 hydrophilic modification by glucuronidation and glucosidation.…”

“…81,82 In addition to CYP2C8-mediated oxidation, roxadustat undergoes phase 2 hydrophilic modification by glucuronidation and glucosidation. 75,83 Enarodustat is also metabolized by CYP enzymes, 72 whereas molidustat and vadadustat are primarily metabolized by uridine 5 0 -diphospho-glucuronosyltransferases. 74,76 Changes in renal function are unlikely to affect elimination rates of nonmodified daprodustat and roxadustat as their renal clearance is low (Table 1).…”