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Pharmacokinetic‐pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers
Author(s) -
Ragueneau Isabelle,
Laveille Christian,
Jochemsen Roeline,
Resplandy Guillemette,
FunckBrentano Christian,
Jaillon Patrice
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90153-9
Subject(s) - ivabradine , pharmacodynamics , pharmacokinetics , nonmem , heart rate , medicine , active metabolite , pharmacology , metabolite , bolus (digestion) , population , anesthesia , antiarrhythmic agent , cardiology , blood pressure , heart disease , environmental health
Objective Ivabradine (S‐16257) is a new bradycardic agent with a direct effect on the sinus node. Its N ‐dealkylated metabolite, S‐18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers. Methods Eighteen healthy volunteers participated in three successive study periods: an oral double‐blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24‐hour postdosing, and ivabradine and S‐18982 plasma levels were determined simultaneously. Results The maximal reductions of exercise heart rate were 11% ± 4% (10 mg) and 18% ± 6% (20 mg) after single oral doses ( p < 0.05) and 18% ± 4% (10 mg) and 27% ± 6% (20 mg) after repeated doses ( p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% ± 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S‐18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action. Conclusion This study shows that ivabradine exerts a dose‐dependent bradycardic effect and that its N ‐dealkylated metabolite contributes to this bradycardic effect. Clinical Pharmacology & Therapeutics (1998) 64 , 192–203; doi: