Razine Mechanism of Action

Anti-Angina.
Pharmacology: Pharmacodynamics: 375 mg tablet: The mechanism of action of Ranolazine is largely unknown. Ranolazine may have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces intracellular sodium accumulation and consequently decreases intracellular calcium overload. Ranolazine, via its action to decrease the late sodium current, is considered to reduce these intracellular ionic imbalances during ischemia. This reduction in cellular calcium overload is expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness. Clinical evidence of inhibition of the late sodium current by Ranolazine is provided by a significant shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of 5 patients with a long QT syndrome (LQT3 having the SCN5A ΔKPQ gene mutation). These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
500 mg tablet: The mechanism of action of Ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain. The QT prolongation effect of Ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.
Pharmacokinetics: 375 mg tablet: After oral administration of Ranolazine, peak plasma concentrations (Cmax) are typically observed between 2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.
500 mg tablet: Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1 g twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of Ranolazine are similar in healthy volunteers. The apparent terminal half-life of Ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with Ranolazine. At steady state over the dose range of 500 to 1 g twice daily, Cmax and AUC0-τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough peak ratio of the Ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of Ranolazine is unaffected by age, gender, or food.
Absorption and Distribution: 375 mg tablet: The mean absolute bioavailability of Ranolazine after oral administration of immediate-release Ranolazine tablets ranged from 35-50%, with large inter-individual variability. Ranolazine exposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state AUC as the dose was increased from 500 mg to 1 g twice daily. In a pharmacokinetic study in healthy volunteers, steady-state Cmax was, on average, approximately 1770 (SD 1040) ng/mL, and steady-state AUC0-12 was, on average, 13,700 (SD 8290) ng·hr/mL following a dose of 500 mg twice daily. Food does not affect the rate and extent of absorption of Ranolazine. Approximately 62% of Ranolazine is bound to plasma proteins, mainly alpha-1 acid glycoprotein and weakly to albumin. The mean steady-state volume of distribution (Vss) is about 180 L.
500 mg tablet: After oral administration of Ranolazine, peak plasma concentrations of Ranolazine are reached between 2 and 5 hours. After oral administration of 14C-Ranolazine as a solution, 73% of the dose is systemically available as Ranolazine or metabolites. The bioavailability of Ranolazine from Ranolazine tablets relative to that from a solution of Ranolazine is 76%. Because Ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of Ranolazine. Food (high-fat breakfast) has no important effect on the Cmax and AUC of Ranolazine. Therefore, Ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 μg/mL, Ranolazine is approximately 62% bound to human plasma proteins.
Elimination: 375 mg tablet: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted unchanged in the urine and feces. Following oral administration of a single 500 mg dose of [14C]-Ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% in feces. Clearance of Ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life is about 2-3 hours after intravenous administration. The terminal half-life at steady state after oral administration of Ranolazine is about 7 hours, due to the absorption rate-limited elimination.
Biotransformation: 375 mg tablet: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults, Ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral 500 mg dose of [14C]-Ranolazine. A large number of metabolites has been identified in human plasma (47 metabolites), urine (>100 metabolites), and feces (25 metabolites). Fourteen primary pathways have been identified of which O-demethylation and N-dealkylation are the most important. In vitro studies using human liver microsomes indicate that Ranolazine is metabolized primarily by CYP3A4, but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolizers, PM) had 62% higher AUC than subjects with CYP2D6 metabolizing capacity (extensive metabolizers, EM). The corresponding difference at the 1 g twice-daily dose was 25%.
Metabolism and Excretion: 500 mg tablet: Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of Ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of Ranolazine, and display apparent half-lives ranging from 6 to 22 hours.
Toxicology: Preclinical Safety Data: 375 mg tablet: Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinical exposure, were as follows: Ranolazine was associated with convulsions and increased mortality in rats and dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinical dose. Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes at exposures slightly greater than those seen in clinical patients. This effect is associated with increased plasma cholesterol concentrations. No similar changes have been identified in humans. No effect on the adreno-cortical axis was noted in humans. In long-term carcinogenicity studies at doses of Ranolazine up to 50 mg/kg/day (150 mg/m²/day) in mice and 150 mg/kg/day (900 mg/m²/day) in rats, no relevant increases in the incidence of any tumor types were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximum recommended human dose of 2 grams on a mg/m² basis, and represent the maximum tolerated doses in these species. Signs of embryonal and maternal toxicity, but not teratogenicity, were seen at doses of Ranolazine up to 400 mg/kg/day (2400 mg/m²/day) in rats and 150 mg/kg/day (1800 mg/m²/day) in rabbits. These doses represent 2.7 and 2 times, respectively, the maximum recommended human dose. Animal studies do not indicate direct or indirect harmful effects of Ranolazine with respect to male or female fertility.
500 mg tablet: Carcinogenesis, Mutagenesis, Impairment of Fertility - Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays. There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m²/day) and 50 mg/kg/day for 24 months in mice (150 mg/m²/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a surface area basis. A published study reported that Ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear; Reproductive Toxicology Studies - Animal reproduction studies with Ranolazine were conducted in rats and rabbits. There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.