Mechanism of Action

The mechanism of action of ranolazine has not been determined. Ranolazine has antianginal and anti-ischemic 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 late I_Na. 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 I_Kr, which prolongs the ventricular action potential.

Pharmacokinetics

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg b.i.d., the mean steady-state Cmax was 2569 ng/mL; 95% of Cmax values were between 420 and 6080 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 b.i.d. dosing with Ranexa. At steady state over the dose range 500 to 1000 mg b.i.d., Cmax and AUC_0-τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice daily dosing, the peak/trough ratio of the ranolazine plasma concentration is 1.6 to 3.0.

Absorption and Distribution

After oral administration of Ranexa, 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 Ranexa relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-glycoprotein (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, Ranexa 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.

Metabolism and Excretion

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 b.i.d., 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. Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6.

Special Populations

Age, Gender, and Race

A population pharmacokinetic evaluation of data from patients and healthy volunteers showed no clinically significant age- or gender-related effects on the pharmacokinetics of ranolazine. Dosage modifications for age or gender are, therefore, not required (see DOSAGE AND ADMINISTRATION). Requirements for dosage modification based on race have not been adequately assessed.

Pediatric

The pharmacokinetics of ranolazine have not been investigated in patients < 18 years of age.

Renal Insufficiency

In a pharmacokinetic study in patients with varying degrees of renal impairment, ranolazine plasma levels appeared to increase about 50%. The pharmacokinetics of ranolazine in patients on dialysis have not been assessed. In six subjects with severe renal impairment on Ranexa 500 mg b.i.d., mean diastolic blood pressure increased approximately 10 to 15 mm Hg.

Hepatic Insufficiency

The disposition of ranolazine administered in a dose of Ranexa 500 mg b.i.d. was studied in 16 subjects with mild or moderate hepatic impairment and 16 healthy volunteers. The plasma concentrations of ranolazine were increased in the subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) liver impairment by factors of 1.3 and 1.6, respectively, relative to the healthy volunteers. In the same study, patients with mild and moderate hepatic impairment had increases in QTc that were larger than those of normal subjects at the same plasma ranolazine level (see Pharmacodynamic Effects).

Congestive Heart Failure

Bookmark this page: