Pharmacology: Pharmacodynamics: Ivabradine: The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm. At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarizatlon: In clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals; in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30 and 45%), ivabradine did not have any deleterious influence on LVEF.
Metoprolol: Metoprolol reduces or inhibits the catecholamines effect on the heart, which leads to a decrease in the rhythm, contractility and cardiac output. Metoprolol has an antihypertensive effect, both in the orthostatic and supine position. It also reduces the rise in blood pressure due to exertion.
Pharmacokinetics: The rate and extent of absorption of ivabradine and metoprolol from Implicor are not significantly different, respectively, from the rate and extent of absorption of ivabradine and metoprolol when taken alone as monotherapy.
Ivabradine: 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 hour 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 hour, and increased plasma exposure by 20 to 30 %. The intake of the tablet during meals is recommended in order to decrease infra-individual variability in exposure.
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 ng/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.
Elimination: Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective half-life of 11 hours. 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/non linearity: The kinetics of ivabradine is linear over an oral dose range of 0.5-24 mg.
Special populations: Older people: No pharmacokinetic differences (AUC and Cmax) have been observed between elderly (≥65 years) or very elderly patients (≥75 years) and the overall population.
Renal impairment: The impact of renal impairment (creatinine clearance from 15 to 60 mL/min) on ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20%) to total elimination for 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: PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to 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.
Metoprolol: Absorption and distribution: Metoprolol is completely absorbed after an oral dose, peak plasma concentrations occurring 1.5-2 hours after dosing. Due to a pronounced first passage metabolism for metoprolol, the bioavailability of a single oral dose is approx. 50%. Concomitant intake of food increases bioavailability by approximately 30-40%. Only a small fraction of metoprolol (approx. 5-10%) binds to plasma proteins.
Biotransformation: Metoprolol is metabolized by hepatic oxidation. The three known main metabolites have been shown not to have a clinically significant beta blocking effect.
Metoprolol is metabolized primarily, but not solely, by the hepatic enzyme cytochrome (CYP) 2D6. Due to the polymorphy of the CYP 2D6 gene, the turnover rates vary with the individual. Individuals with poor metabolic capacity (approx. 7-8%) exhibit higher plasma concentrations and slower elimination than individuals with good metabolic capacity.
Elimination: The plasma concentrations are stable and repeatable in the individuals, however more than 95% of an oral dose is excreted in the urine. Approximately 5% of the dose is excreted in uncharged form: In single cases up to an entire 30%. The elimination half-life of metoprolol in plasma is 3.5 hours on average (interval 1-9 hours). Total clearance is approximately 1 L/min.
Special populations: Older people: The pharmacokinetics of metoprolol in the elderly is not significantly different from that in younger populations.
Hepatic impairment: Increased bioavailability and decreased total clearance.
Pregnancy: Metoprolol crosses into the placenta. The mean ratio of cord blood/maternal blood metoprolol concentration is 1.
Lactation: Metoprolol is excreted in breast milk; the mean ratio of maternal milk/maternal blood metoprolol concentration is 3.7.