Gavrila Mechanism of Action

Pharmacology: Pharmacokinetics: Under physiological conditions, Ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/mL). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of Ivabradine has been identified as the main active metabolite in humans.
Absorption and Bioavailability: Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hr under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hr and increased plasma exposure by 20-30%. The intake of the tablet during meals is recommended in order the decrease intraindividual variability in exposure (see Dosage & Administration).
Distribution: Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady state is close to 100 L in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/mL (CV=29%). The average plasma concentration is 10 mg/mL (CV=38%) at steady state.
Biotransformation: Ivabradine is extensively metabolized by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect Ivabradine plasma concentrations (see Interactions).
Elimination: Ivabradine is eliminated with main t½ of 2 hrs (70-75% of the AUC) in plasma and an effective t½ of 11 hrs. The total clearance is about 400 mL/min and the renal clearance is about 70 mL/min. Excretion of metabolites occurs to a similar extent via feces and urine. About 4% of an oral dose is excreted unchanged in urine.
Linearity/Nonlinearity: The kinetics of Ivabradine is linear over an oral dose range of 0.5-24 mg.
Special Populations: Elderly: No pharmacokinetic differences (AUC and C_max) have been observed between elderly (65 years) or very elderly patients (75 years) and the overall population.
Renal Insufficiency: The impact of renal impairment (creatinine clearance from 15-60 mL/min) on Ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20%) to total elimination of both Ivabradine and its main metabolite S 18982.
Hepatic Impairment: In patients with mild hepatic impairment (Child Pugh score up to 7) unbound AUC of Ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function. Data are insufficient to draw conclusions in patients with moderate hepatic impairment.
No data are available in patients with severe hepatic impairment.
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship: Pharmacokinetic/Pharmacodynamic relationship analysis has shown that heart rate decreases almost linearly with increasing Ivabradine and S18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional Ivabradine plasma concentrations and tends to reach a plateau. High exposures to Ivabradine that may occur when Ivabradine is given in combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate, although this risk is reduced with moderate CYP3A4 inhibitors.