Pharmacokinetic and Pharmacodynamic Properties of Cinacalcet (KRN1493) in Chinese Healthy Volunteers: A Randomized, Open-label, Single Ascending–dose and Multiple-dose, Parallel-group Study

Li, Hongzhong; Wang, Hongyun; Liu, Tao; Jiang, Ji; Chen, Xia; Gao, Feng; Hu, Pei

doi:10.1016/j.clinthera.2015.12.015

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…In the multiple-dose study, the C trough values were relatively unchanged at Days 1–8, showing no accumulation. Similarly, no accumulation has been reported for cinacalcet [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

et al. 2018

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Background and ObjectivesEvocalcet is a novel calcimimetic agent with potential to improve the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. This study aimed to determine the pharmacokinetics, pharmacodynamics, and safety of evocalcet in healthy Japanese subjects.MethodsThis was a single-blind, placebo-controlled, single-dose study and an 8-day multiple-dose study of evocalcet (MT-4580/KHK7580) in 66 healthy Japanese subjects.ResultsAfter a single dose of evocalcet 1–20 mg, the time to maximum plasma concentration was attained in 1.5–2 h (median), and the elimination half-life was 12.98–19.77 h (mean). Within this dose range, the maximum plasma concentration and area under plasma concentration-time curve increased dose proportionally, confirming linearity. The trough plasma concentrations were relatively unchanged after multiple administration of evocalcet 6 and 12 mg. Evocalcet decreased intact parathyroid hormone and corrected calcium and phosphorus levels in a dose-proportional manner. Regarding its safety, no upper gastrointestinal adverse event occurred after the single and multiple administration of evocalcet at doses up to 12 mg. Tetany was detected in 1 subject (17%) after multiple administration of evocalcet 12 mg. In healthy subjects, the tolerability and safety of evocalcet were observed for a single dose of evocalcet at doses up to 20 mg, and for multiple doses up to 12 mg.ConclusionsThese results suggest that evocalcet may have a comparable efficacy and better safety profile than that of cinacalcet, one of the current treatments for secondary hyperparathyroidism in patients with chronic kidney disease.Electronic supplementary materialThe online version of this article (10.1007/s40261-018-0687-4) contains supplementary material, which is available to authorized users.

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“…In the multiple-dose study, the C trough values were relatively unchanged at Days 1–8, showing no accumulation. Similarly, no accumulation has been reported for cinacalcet [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

et al. 2018

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“…There are limited reports of cinacalcet AEs occurring in healthy subjects. The most frequently occurring AE observed in our study was hypocalcemia, followed by changes in plasma iPTH (37,38).…”

Section: Discussionmentioning

confidence: 55%

Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects

et al. 2020

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Background: Our study aims to explore the effect of genetics on the pharmacodynamics (PD) and pharmacokinetics (PK) of cinacalcet in healthy Chinese subjects; to investigate the effect of dietary factors on cinacalcet, and to evaluate the safety of cinacalcet under fasting and non-fasting conditions using a bioequivalence trial. Methods: We investigated the relationship of cinacalcet PK with single nucleotide polymorphisms (SNPs) of CYP3A4, CYP1A2 and CYP2D6, and of cinacalcet PD with SNPs of calcium-sensitive receptors (CASR) and vitamin D receptors (VDR) in 65 healthy Chinese subjects recruited to participate in this study. Our study was a phase I, open-label, randomized, two-period, two-sequence crossover, a single-center clinical study designed under both fasting and non-fasting conditions to investigate the effect of dietary factors on cinacalcet. Plasma cinacalcet concentrations were analyzed using a validated HPLC-MS/MS assay. Clinical laboratory tests evaluated safety. Thirteen SNPs of CASR, VDR, and CYP genes were selected for pharmacogenetic analysis.Results: CYP3A4 rs4646437 was found to be associated with the PK of cinacalcet under fasting conditions (P<0.01). Subjects carrying T alleles of rs4646437 appeared to metabolize cinacalcet poorly. The C max and AUC of subjects in the non-fasting group were significantly higher (P<0.0001) than those in the fasting group. The T max , CL/F, and Vd/F in the fasting group were significantly higher (P<0.0001) than those in the non-fasting group. In the fasting group, the geometric least square mean ratios (T/R) of the C max and AUC 0-t were 109.89% and 105.33%, and the corresponding 90% CIs were 98.36-122.79% and 98.04-113.15%, respectively. In the non-fasting group, the T/R of the C max and AUC 0-t were 100.74% and 99.09%, and the corresponding 90% CIs were 92.65-109.54% and 94.79-103.58%, respectively. All adverse events (AEs) were mild, and no serious adverse events (SAEs) occurred during the bioequivalence trial.Conclusions: Following our investigation, we reached the following conclusions: CYP3A4 rs4646437 may affect cinacalcet PK; the reference and test preparations of cinacalcet were bioequivalent under fasting and non-fasting conditions and were safe to use; and dietary factors had a significant effect on the PK of cinacalcet, in that exposure to the drug increased when cinacalcet was taken after eating.

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“…Cinacalcet hydrochloride (CIN) is the first agent of a new therapeutic class of calcimimetic compounds, which act by increasing the sensitivity of calcium-sensing receptors to the extracellular calcium ions, thus lowering the release of parathyroid hormone [1]. CIN is an approved medication for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease on dialysis and hypercalcemia in patients with parathyroid carcinoma [2].…”

Section: Introductionmentioning

confidence: 99%

Chiral capillary zone electrophoresis in enantioseparation and analysis of cinacalcet impurities: Use of Quality by Design principles in method development

Pasquini

Orlandini

Villar-Navarro

et al. 2018

Journal of Chromatography A

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Pharmacokinetic and Pharmacodynamic Properties of Cinacalcet (KRN1493) in Chinese Healthy Volunteers: A Randomized, Open-label, Single Ascending–dose and Multiple-dose, Parallel-group Study

Cited by 7 publications

References 23 publications

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects

Chiral capillary zone electrophoresis in enantioseparation and analysis of cinacalcet impurities: Use of Quality by Design principles in method development

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