Pharmacokinetic and Safety Profile of Ivabradine in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Increasing Single- and Multiple-Dose Study

Jiang, Juanjuan; Tian, Lei; Huang, Ye; Li, Yishi; Xu, Li

doi:10.1016/j.clinthera.2013.10.007

Cited by 16 publications

(24 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, when a 30‐mg oral dose of ivabradine has been administered to healthy volunteers, a mean maximum plasma level of 0.17 μmol/L has been reported 36 and, in a separate study, multiple dosing with 5 to 20 mg of ivabradine resulted in plasma C max values of 34 to 137 nmol/L. 37 In the present study, ivabradine concentrations (100 to 500 nmol/L) overlapping this range affected MAPD 50 and MAPD 90 and effective refractory period in a concentration‐dependent fashion, in both apex and base of the guinea‐pig left ventricle. It is unclear why the effects of ivabradine seen here are more marked than some previous studies; however, the use of different species and/or preparations may contribute.…”

Section: Discussionmentioning

confidence: 99%

hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

Melgari¹,

Brack

Zhang

et al. 2015

JAHA

106

View full text Add to dashboard Cite

BackgroundIvabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN‐channels. This study investigated the propensity of ivabradine to interact with KCNH2‐encoded human Ether‐à‐go‐go–Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia.Methods and ResultsPatch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. IhERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time‐dependent characteristics of IhERG block were consistent with preferential gated‐state‐dependent channel block. Inhibition was partially attenuated by the N588K inactivation‐mutant and the S624A pore‐helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK‐based homology model of hERG, the 2 aromatic rings of the drug could form multiple π‐π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea‐pig Langendorff‐perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve.ConclusionsIvabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits IhERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design.

show abstract

Section: Discussionmentioning

confidence: 99%

hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

Melgari¹,

Brack

Zhang

et al. 2015

JAHA

106

View full text Add to dashboard Cite

show abstract

“…In the Discussion of their paper, Lees-Miller and colleagues highlight some similarities and differences between their findings [1] and our own recent report [2]: both studies provide These results are intriguing, and the notion that the drug may accumulate in lipid is attractive, because at clinically relevant plasma levels of the drug [7] comparatively little inhibition of either HCN4 or hERG channels might be anticipated and yet the drug is clearly clinically effective at slowing heart rate. Interesting questions arise, however, as to the likely contribution of the second novel potential interaction site and regarding the gating dependence of the drug's inhibitory effect on hERG.…”

mentioning

confidence: 83%

hERG potassium channel inhibition by ivabradine requires channel gating

Melgari

Brack

Zhang

et al. 2015

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

“…Our findings in healthy participants cannot be simply extrapolated to patients. Finally, given the potential influence of respiration on postganglionic sympathetic discharge, it would have been desirable to also record and analyze breathing, yet others did not observe effects of ivabradine on respiratory rate either in healthy men or in patients with chronic obstructive pulmonary disease…”

Section: Discussionmentioning

confidence: 99%

Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping

Heusser

Tank

Brinkmann

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundSympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.Methods and ResultsWe treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.ConclusionsHCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.

show abstract

Pharmacokinetic and Safety Profile of Ivabradine in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Increasing Single- and Multiple-Dose Study

Cited by 16 publications

References 9 publications

hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

hERG potassium channel inhibition by ivabradine requires channel gating

Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping

Contact Info

Product

Resources

About