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

Autor: Pai SM; Clinical Pharmacology, Akros Pharma, Inc., Princeton, New Jersey, USA., Yamada H; Clinical Pharmacology, Japan Tobacco Inc., Pharmaceutical Division, Tokyo, Japan., Kleiman RB; ERT, 1818 Market Street, 10th floor, Philadelphia, Pennsylvania, USA., Zhuo R; Biostatistics, Akros Pharma, Inc., Princeton, New Jersey, USA., Huang QM; Clinical Pharmacology, Akros Pharma, Inc., Princeton, New Jersey, USA., Koretomo R; Clinical Development, Japan Tobacco Inc., Pharmaceutical Division, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2021 Aug; Vol. 10 (8), pp. 884-898. Date of Electronic Publication: 2021 Jun 23.
DOI: 10.1002/cpdd.933
Abstrakt: 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.
(© 2021, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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