Ivabradine Pharmacokinetics and Pharmacodynamics
Ivabradine selectively reduces heart rate by blocking the If current in the sinoatrial node through inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, with linear pharmacokinetics, approximately 40% oral bioavailability, and extensive CYP3A4-mediated metabolism to an equipotent active metabolite. 1
Pharmacodynamics
Mechanism of Action
Ivabradine blocks the cardiac pacemaker If current by inhibiting HCN channels, which slows the diastolic depolarization phase in sinoatrial node cells 1. This mechanism is "use-dependent"—meaning greater heart rate reduction occurs at higher baseline heart rates and less reduction at lower baseline rates 2.
Key pharmacodynamic effects:
- Heart rate reduction: Approximately 10 bpm at rest and during exercise at recommended doses 1
- Dose-dependent effect: Analysis shows a plateau effect at doses >20 mg twice daily 1
- No negative inotropic or lusitropic effects: Ivabradine does not impair myocardial contractility 2, 1
- Conduction effects: In patients with preexisting conduction disease, IV ivabradine increased PR interval by 29 msec and AH interval by 27 msec 1
- QT interval: Increases uncorrected QT with heart rate slowing but does not cause rate-corrected QT prolongation 1
Retinal Effects
Ivabradine also inhibits the retinal Ih current, which curtails retinal responses to bright light 1. This causes phosphenes (transient enhanced brightness in limited visual field areas) in 5.4% of patients, though these are mild, transitory, and rarely lead to treatment withdrawal (<1%) 2.
Pharmacokinetics
Absorption and Bioavailability
- Tmax: Peak plasma concentrations reached in approximately 1 hour under fasting conditions 1
- Oral bioavailability: Approximately 40% due to first-pass elimination in gut and liver 1
- Food effect: Food delays absorption by ~1 hour and increases plasma exposure by 20-40%; ivabradine should be taken with food 1
- Protein binding: Approximately 70% plasma protein bound 1
- Volume of distribution: Approximately 100 L at steady state 1
Metabolism and Elimination
Ivabradine is extensively metabolized via CYP3A4-mediated oxidation in the liver and intestines 1. The major metabolite is the N-desmethylated derivative (S-18982), which is:
- Equipotent to ivabradine 1
- Circulates at concentrations approximately 40% of parent drug 1
- Also metabolized by CYP3A4 1
Elimination parameters:
- Distribution half-life: 2 hours 1
- Effective half-life: Approximately 6 hours 1
- Total clearance: 24 L/h 1
- Renal clearance: Approximately 4.2 L/h, with ~4% excreted unchanged in urine 1
- Excretion route: Metabolites excreted equally via feces and urine 1
Linearity
Pharmacokinetics are linear over an oral dose range of 0.5 mg to 24 mg 1.
Special Populations
- Age: No pharmacokinetic differences in elderly (≥65 years) or very elderly (≥75 years) patients 1
- Hepatic impairment: Similar pharmacokinetics in mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment; no data for severe impairment (Child-Pugh C) 1
- Renal impairment: Minimal effect with creatinine clearance 15-60 mL/min; no data for CrCl <15 mL/min 1
- Pediatrics: Weight and age effects on clearance and volume; maturation function affects metabolite formation clearance reflecting enzyme maturation 3
Pharmacokinetic/Pharmacodynamic Relationship
Both ivabradine and its metabolite S-18982 contribute to bradycardic activity 4. Population modeling suggests:
- The metabolite is responsible for the initial bradycardic effect
- The parent compound is responsible for the duration of action 4
The PK/PD relationship established in adults is conserved in children 3.
Critical Drug Interactions
Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, diltiazem, verapamil) as they significantly increase ivabradine exposure and risk of excessive bradycardia 2, 1. The European Medicines Agency specifically contraindicates use with diltiazem or verapamil due to excess bradycardia risk observed in the SIGNIFY trial 2.
No dose adjustment required for: