Chemical formula: C₂₄H₃₃N₃O₄ Molecular mass: 427.537 g/mol PubChem compound: 56959
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 ischaemia. 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 ∆KPQ gene mutation).
These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
Minimal decreases in mean heart rate (<2 beats per minute) and mean systolic blood pressure (<3 mmHg) were observed in patients treated with ranolazine either alone or in combination with other antianginal medicinal products in controlled studies.
Dose and plasma concentration-related increases in the QTc interval (about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched T waves, have been observed in patients treated with ranolazine. These effects of ranolazine on the surface electrocardiogram are believed to result from inhibition of the fast-rectifying potassium current, which prolongs the ventricular action potential, and from inhibition of the late sodium current, which shortens the ventricular action potential. A population analysis of combined data from 1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msec per 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotal clinical studies, where mean changes from baseline in QTcF (Fridericia’s correction) after doses of 500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients with clinically significant hepatic impairment.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no difference between ranolazine and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99), sudden cardiac death (relative risk ranolazine:placebo 0.87), or the frequency of symptomatic documented arrhythmias (3.0% versus 3.1%).
No proarrhythmic effects were observed in 3,162 patients treated with ranolazine based on 7-day Holter monitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmias in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia ≥8 beats (5% versus 8%).
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.
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 1000 mg 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 x h/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.
Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted unchanged in the urine and faeces. 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 faeces.
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.
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 faeces (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 metabolised primarily by CYP3A4, but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolisers, PM) had 62% higher AUC than subjects with CYP2D6 metabolising capacity (extensive metabolisers, EM). The corresponding difference at the 1000 mg twice-daily dose was 25%.
The influence of various factors on the pharmacokinetics of ranolazine was assessed in a population pharmacokinetic evaluation in 928 angina patients and healthy subjects.
Gender had no clinically relevant effect on pharmacokinetic parameters.
Age alone had no clinically relevant effect on pharmacokinetic parameters. However, the elderly may have increased ranolazine exposure due to age-related decrease in renal function.
Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold higher in subjects weighing 40 kg.
CHF NYHA Class III and IV were estimated to have about 1.3-fold higher plasma concentrations.
In a study evaluating the influence of renal function on ranolazine pharmacokinetics, ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild, moderate, and severe renal impairment compared with subjects with normal renal function. There was a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites increased with decreased renal function. The AUC of one pharmacologically active ranolazine metabolite was 5-fold increased in patients with severe renal impairment.
In the population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was estimated in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal impairment (creatinine clearance 10–30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure was estimated. The influence of dialysis on the pharmacokinetics of ranolazine has not been evaluated.
The pharmacokinetics of ranolazine have been evaluated in patients with mild or moderate hepatic impairment. There are no data in patients with severe hepatic impairment. Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in patients with moderate impairment. QT prolongation was more pronounced in these patients.
The pharmacokinetic parameters of ranolazine have not been studied in the paediatric population (<18 years).
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 tumour 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.
In male and female rats, oral administration of ranolazine that produced exposures (AUC) 3.6-fold or 6.6-fold higher than expected in humans, respectively, had no effect on fertility.
Embryofetal toxicity studies were conducted in rats and rabbits: no effect were noted in rabbit fetuses when mothers were exposed at levels (AUC) of plasma ranolazine similar to expected human levels. In rats, no effects in fetuses was noted when mothers were exposed to 2-fold greater levels (AUC) than expected in humans, whereas decreased fetal weight and reduced ossification were observed when the exposure of mothers was 7.5-fold than those obtained in humans. Post-natal mortality of pups was not recorded when the exposure of nursing mothers was 1.3 fold higher than in expected humans, whereas at 3-fold higher exposure post-natal mortality was recorded, concomitant with evidence of milk excretion of ranolazine in rats. No adverse effects on newborn rats were observed at levels of exposures similar to those observed in humans.
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