Thorough QT/QTc Evaluation of the Cardiac Safety of Enarodustat (JTZ-951), an Oral Erythropoiesis-Stimulating Agent, in Healthy Adults.

This study evaluated the effect of enarodustat on cardiac repolarization in healthy subjects. Enarodustat (20 and 150 mg [supratherapeutic dose]), placebo, and moxifloxacin (positive control, 400 mg) were administered orally to males and females (N = 54) in a crossover fashion. Continuous 12-lead Holter electrocardiogram (ECG) data were obtained before and after dosing, and blood samples were obtained for pharmacokinetic assessments of enarodustat, its circulating metabolite (R)-M2, and moxifloxacin. Central tendency analysis was performed for relevant ECG parameters, the relationship between individual-corrected interval from beginning of the QRS complex to end of the T wave in the frontal plane (QTcI, the primary end point) and plasma concentrations of enarodustat and (R)-M2 were assessed, and ECG waveforms were evaluated for morphological changes. The supratherapeutic dose resulted in 7- and 9-fold higher geometric mean maximum concentrations for enarodustat and (R)-M2, respectively, than the 20 mg dose. Based on time point analysis, the upper bound of the 2-sided 90% confidence interval (CI) for QTcI did not exceed 10 milliseconds at any of the time points for either dose. Based on QTcI-concentration analysis, the slopes for enarodustat and (R)-M2 were not statistically different than 0, and the upper bounds of the 2-sided 90% CI for QTcI at the geometric mean maximum concentrations for the supratherapeutic dose were 1.97 and 1.68 milliseconds for enarodustat and (R)-M2, respectively. The lower bound of the 2-sided 90% CI for moxifloxacin was ≥5 milliseconds, demonstrating assay sensitivity. The study demonstrated no clinically relevant effect of enarodustat and (R)-M2 on cardiac repolarization. There was no evidence of any clinically significant effect on the PR interval and QRS duration, and ECG waveforms showed no new clinically relevant morphological changes.

A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma.

Enarodustat, a potent, orally bioavailable, selective inhibitor of hypoxia inducible factor-Prolyl hydroxylase (HIF-PH), has been approved recently in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). To evaluate the pharmacokinetics of enarodustat, a bioanalytical assay in human plasma was needed for the quantitation of enarodustat for both healthy subjects and patients with CKD. The UPLC-MS/MS method for the quantitation of enarodustat was initially validated in a bioanalytical laboratory in Japan to support clinical studies conducted in Japan, and then was transferred and validated in a bioanalytical laboratory in United States to support clinical studies conducted here. A cross-validation was successfully performed between the two bioanalytical laboratories using both quality control (QC) samples and incurred study samples. Enarodustat was fortified with its isotopically labeled internal standard in a 25 µL plasma aliquot and extracted with protein precipitation. The chromatographic separation was achieved on an Acquity UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column with gradient elution. The calibration curve range for the assay was 1.00-500 ng/mL. Assay precision, accuracy, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. No interferences were observed from medications that may be co-administered along with enarodustat. The validated UPLC-MS-MS method at the US bioanalytical laboratory has been successfully applied to eight clinical studies for the determination of enarodustat concentrations in human plasma for both healthy subjects and patients with CKD.

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

The dialysis clearance of enarodustat (JTZ-951) was determined in patients (N = 6) with end-stage renal disease on hemodialysis. Enarodustat (5 mg PO) was administered before (day 1) and after hemodialysis (day 8) with pharmacokinetic assessments on the 2 occasions. Dialysis clearance was based on plasma and dialysate enarodustat concentrations. Fraction of administered dose recovered in dialysate, total predialyzer and postdialyzer plasma enarodustat concentrations, and total and unbound venous plasma concentrations were determined. Hemodialysis did not significantly affect overall total concentrations with similar mean area under the plasma concentration-time curve from time 0 to infinity (coefficient of variation) of 3350 (26.4%) and 3640 (20.9%) ng · h/mL on days 1 and 8, respectively, and mean terminal half-life was 9.35 (11.9%) and 9.96 (18.7%) hours on the 2 occasions. Mean maximum concentration was somewhat lower on day 1 compared to day 8 (404 vs 559 ng/mL); the difference did not significantly affect total exposure (area under the plasma concentration-time curve from time 0 to infinity). Plasma protein binding was high (>99%) with similar binding on the 2 occasions, and total pre- and postdialyzer enarodustat concentrations were similar. Plasma unbound enarodustat concentrations decreased during dialysis, with a postdialysis rebound presumably due to re-equilibration with peripheral tissues. Mean unbound area under the plasma concentration-time curve from time 0 to infinity was marginally lower (∼22%) on day 1 compared to day 8. Dialysis clearance (0.415 L/h) was insignificant relative to dialyzer plasma flow (∼20 L/h), and the fraction of administered dose recovered in dialysate was small (6.74% of dose) with low intersubject variability (coefficient of variation, 14.7%). Thus, enarodustat can be administered regardless of dialysis schedule, and dose supplementation is not required in patients with end-stage renal disease on hemodialysis.

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

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.