1. The effect of fluvoxamine on the pharmacokinetics, and safety of ivabradine in healthy subjects Adina Popa 1, Laurian Vlase 2, Maria Neag 3, Dana Muntean 2, Sorin E. Leucuta 2 University of Medicine and Pharmacy „Iuliu Hatieganu 1 Department of Clinical Pharmacy, 2 Department of Pharmaceutical Technology and Biopharmaceutics, 3 Department of Pharmacology, Toxicology and Clinical Pharmacology INTRODUCTION Ivabradine (IVA) is the first of a new class of heart rate-lowering agents that act specifically on the sinoatrial node. It selectively inhibits the If current of cardiac pacemaker cells without affecting other cardiac ionic currents. IVA is an effective anti-anginal agent. Some findings suggest that lowering heart rate with IVA achieves reduction of major morbidity and mortality, as well as improvements in health related quality of life for cardiac failure patients. IVA is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. Fluvoxamine (FLUV) is a second-generation antidepressant that selectively inhibits neuronal reuptake of serotonin. FLUV is a potent inhibitor of CYP1A2 and CYP2C19, and shows moderate potency as an inhibitor of CYP2C9 and CYP3A4; it only slightly affects CYP2D6 activity. As a consequence of its non-selective inhibition of various CYP isozymes, FLUV has the potential for clinically significant pharmacokinetic interactions INTRODUCTION Ivabradine (IVA) is the first of a new class of heart rate-lowering agents that act specifically on the sinoatrial node. It selectively inhibits the If current of cardiac pacemaker cells without affecting other cardiac ionic currents. IVA is an effective anti-anginal agent. Some findings suggest that lowering heart rate with IVA achieves reduction of major morbidity and mortality, as well as improvements in health related quality of life for cardiac failure patients. IVA is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. Fluvoxamine (FLUV) is a second-generation antidepressant that selectively inhibits neuronal reuptake of serotonin. FLUV is a potent inhibitor of CYP1A2 and CYP2C19, and shows moderate potency as an inhibitor of CYP2C9 and CYP3A4; it only slightly affects CYP2D6 activity. As a consequence of its non-selective inhibition of various CYP isozymes, FLUV has the potential for clinically significant pharmacokinetic interactions OBJECTIVE To investigate the effects of multiple doses of FLUV on the pharmacokinetics (Pk), and safety of a single oral 10 mg dose of IVA. OBJECTIVE To investigate the effects of multiple doses of FLUV on the pharmacokinetics (Pk), and safety of a single oral 10 mg dose of IVA. METHODS Study design An open, 2-period, nonrandomized, Pk interaction design was used. The study was approved by Ethics Committee of the University. Bioanalysis 5 ml samples of venous blood were collected at pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hours post-dose on days 1 and 8. Plasma concentrations of IVA were determined by means of a validated high throughput liquid chromatography-mass spectrometry method. Pharmacokinetic analysis The noncompartmental Pk analysis method was employed to determine the Pk parameters of IVA given alone or in combination with FLUV. The Pk analysis was performed using Kinetica 4.2 (Thermo Labsystems, U.S.A.). Statistical analysis The analysis of variance (ANOVA) was used to compare the Pk parameters of IVA in combination with FLUV relative to IVA alone. The statistical analysis was performed using Kinetica 4.2 software. METHODS Study design An open, 2-period, nonrandomized, Pk interaction design was used. The study was approved by Ethics Committee of the University. Bioanalysis 5 ml samples of venous blood were collected at pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hours post-dose on days 1 and 8. Plasma concentrations of IVA were determined by means of a validated high throughput liquid chromatography-mass spectrometry method. Pharmacokinetic analysis The noncompartmental Pk analysis method was employed to determine the Pk parameters of IVA given alone or in combination with FLUV. The Pk analysis was performed using Kinetica 4.2 (Thermo Labsystems, U.S.A.). Statistical analysis The analysis of variance (ANOVA) was used to compare the Pk parameters of IVA in combination with FLUV relative to IVA alone. The statistical analysis was performed using Kinetica 4.2 software. RESULTS Demographic, and safety A total of 20 subjects, healthy male and female, were enrolled in the study. The mean age, body weight, height, and body mass index (BMI) of the subjects were 24 years (range 21-39 years), 72.18 kg (range 50–96 kg), 1.73 m (range 1.6-1.9 m), and 24.22 (range 18.6-28) respectively. All subjects were treated, and all completed the study. There were no serious adverse events and no subjects withdrew from the study. Analysis of vital signs, electrocardiogram (ECG) and safety laboratory parameters did not reveal any safety concerns. Pharmacokinetics RESULTS Demographic, and safety A total of 20 subjects, healthy male and female, were enrolled in the study. The mean age, body weight, height, and body mass index (BMI) of the subjects were 24 years (range 21-39 years), 72.18 kg (range 50–96 kg), 1.73 m (range 1.6-1.9 m), and 24.22 (range 18.6-28) respectively. All subjects were treated, and all completed the study. There were no serious adverse events and no subjects withdrew from the study. Analysis of vital signs, electrocardiogram (ECG) and safety laboratory parameters did not reveal any safety concerns. Pharmacokinetics Mean (±SD) plasma levels of IVA given alone (continuous line) or in combination with FLUV (dotted line); in insert semilogaritmic presentation. Pk parameter (±SD) IVAIVA + FLUV p* value, ANOVA C max (ng/ml)18.2±8.3031.3±11.20.0024 t max (hr)1.2±0.71.1±0.70.411** AUC 0-t (ng.hr/ml)58.9±19.4118.7±45.30.0002 AUC 0-  (ng.hr/ml)61.4±19.4123.1±46.50.0002 k el (1/hr)0.37±0.080.29±0.060.036 t ½ (hr)1.9±0.52.5±0.60.036 MRT (hr)3.5±0.63.88±0.60.150 * significance for p<0.05, ** Wilcoxon signed-rank test Mean values of Pk parameters of IVA alone or after treatment with FLUV and the result of statistical test CONCLUSION Co-administration of the CYP3A4 inhibitor FLUV with IVA resulted in an interaction. Increased plasma concentrations of IVA may be associated with the risk of excessive bradycardia. However, the safety data collected during the study do not indicate that this interaction will cause any major safety concerns. CONCLUSION Co-administration of the CYP3A4 inhibitor FLUV with IVA resulted in an interaction. Increased plasma concentrations of IVA may be associated with the risk of excessive bradycardia. However, the safety data collected during the study do not indicate that this interaction will cause any major safety concerns.