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Enarodustat is an orally available hypoxia‐inducible factor‐prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non‐calcium‐based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open‐label, crossover study in healthy male subjects (N = 12) that evaluated the effect of sevelamer carbonate (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study. [ABSTRACT FROM AUTHOR]

The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once‐daily administration for 15 days in a phase 1 multiple‐ascending‐dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day −3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve from the time of dosing to infinity (AUCinf) ratios (day 15/day −3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99–1.06 and 1.61–1.63, respectively. The ratios for peak concentrations and total exposures were 0.98–1.07 and 0.71–1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83–0.90 and 1.02–1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day −3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42–1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80–1.25 range, but changes in the geometric mean ratios were all <2‐fold. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end‐stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non‐Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration‐time curve from the time of dosing to infinity were dose‐dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2 of <10 hours indicated negligible accumulation with once‐daily dosing. In general, with daily dosing (25, 50 mg), accumulation at steady‐state was ≈1.5‐fold (t1/2(eff) ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single‐ and multiple‐dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non‐Japanese patients with ESRD on hemodialysis, following once‐daily dosing (2–15 mg), enarodustat was rapidly absorbed, steady‐state maximum plasma concentration and area under the plasma concentration‐time curve during the dosing interval were dose‐dependent, and interindividual variability in the exposure parameters was low‐to‐moderate (coefficient of variation, 27%–39%). Steady‐state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2 and t1/2(eff) were similar (overall, 8.97–11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15 mg, single dose) exhibited similar pharmacokinetics with mean t1/2 of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non‐Japanese patients. Body weight‐adjusted clearance values were generally similar in non‐Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 14C‐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. [ABSTRACT FROM AUTHOR]