Pharmacokinetics and Safety of Extended-release Ranolazine in Korean and White Healthy Subjects.

PURPOSE: Ranolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects. METHODS: An open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375-750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for Cmax, Cmax,ss, AUClast, and AUC0-12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study. FINDINGS: A total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups. IMPLICATIONS: The PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932.

Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis.

PURPOSE: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. METHODS: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. RESULTS: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. CONCLUSIONS: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Persistence of a Posaconazole-Mediated Drug-Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety.

The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half-life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal-weight and obese subjects for 7-14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after discontinuation of a strong CYP3A inhibitor before ranolazine can be safely administered. We recommend that administration of ranolazine should be limited to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with body mass index 18.5-24.9 kg/m2 and for 12 days in patients with body mass index ≥35 kg/m2 after ranolazine is resumed.

Formulation and Coating of Alginate and Alginate-Hydroxypropylcellulose Pellets Containing Ranolazine.

The formulation and the coating composition of biopolymeric pellets containing ranolazine were studied to improve their technological and biopharmaceutical properties. Eudragit L100 (EU L100) and Eudragit L30 D-55-coated alginate and alginate-hydroxypropylcellulose (HPC) pellets were prepared by ionotropic gelation using 3 concentrations of HPC (0.50%, 0.65%, and 1.00% wt/wt) and applying different percentages (5%, 10%, 20%, and 30% wt/wt) of coating material. The uncoated pellets were regular in shape and had mean diameter between 1490 and 1570 µm. The rate and the entity of the swelling process were affected by the polymeric composition: increasing the HPC concentration, the structure of the pellets became more compact and slowed down the penetration of fluids. Coated alginate-HPC formulations were able to control the drug release at neutral pH: a higher quantity of HPC in the system determined a slower release of the drug. The nature of the coating polymer and the coating level applied affected the drug release in acidic environment: EU L100 gave better performance than Eudragit L30 D-55 and the best coating level was 20%. The pellets containing 0.65% of HPC and coated with 20% EU L100 represented the best formulation, able to limit the drug release in acidic environment and to control it at pH 6.8.

Pharmacological Management of Chronic Stable Angina: Focus on Ranolazine.

Percutaneous coronary intervention and anti-anginal medications have similar prognostic effectiveness in patients with chronic stable angina. The choice of optimal medical therapy for the management of chronic angina is of pivotal importance in patients with stable ischemic heart disease. The most commonly used anti-anginal agents have demonstrated equivalent efficacy in improving patient reported ischemic symptoms and quantitative exercise parameters. With regards to mortality, beta-blockers are beneficial only in the setting of depressed left ventricular systolic function after a recent myocardial infarction. Recent evidence suggests the lack of any benefit of beta-blockers in patients with preserved systolic function, even in the setting of prior myocardial infarction.Ranolazine is a non-haemodynamic anti-anginal agent. It is effective as adjunctive therapy in patients with chronic stable angina whose symptoms are un-adequately controlled by conventional treatment. The clinical development program of ranolazine has shown that the drug improves exercise performance, decreases angina and use of sublingual nitrates, compared to placebo. Ranolazine is well tolerated with neutral effect on haemodynamics. Besides its role in chronic stable angina, ranolazine has the potential for development in a number of other cardiovascular and non-cardiovascular conditions in the future.

Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin.

AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear.

Organic Cation Transporter-Mediated Clearance of Cardiovascular Drugs: A Pharmacological Perspective.

There exist a number of mechanisms to clear xenobiotics from human circulation. For cationic drugs, clearance is performed by human organic cation transporters 1 and 2 (hOCT1 and hOCT2), which are expressed in the liver and kidney, respectively. Given the prevalence of patients taking cardiovascular drugs, the present review focuses on the elimination of circulating cardiovascular drugs by organic cation transporters (OCTs). A significant number of cardiovascular drugs compete for transport by OCT1 or OCT2, introducing the potential to alter the pharmacokinetic profile of other concomitantly administered medications. The OCT system thereby represents an important site of drug-drug interactions.

Comparison of the pharmacodynamic effects of ranolazine versus amlodipine on platelet reactivity in stable patients with coronary artery disease treated with dual antiplatelet therapy : The ROMAN (RanOlazine vs. aMlodipine on platelet reactivity in stable patients with CAD treated with dual ANtiplatelet therapy) study.

Amlodipine, commonly used for relief of ischemic symptoms in coronary artery disease (CAD), may affect clopidogrel-induced antiplatelet effects. It remains unknown if ranolazine, an antianginal drug that constitutes a pharmacologic alternative to calcium channel blockade, interferes with clopidogrel-induced antiplatelet effects. The aim of the ROMAN study was to compare the pharmacodynamic effects of ranolazine versus amlodipine on platelet reactivity in clopidogrel treated patients with CAD. A prospective, randomized, cross-over, open-label study conducted in a total of 210 CAD patients on aspirin (100 mg/q.d.) and clopidogrel (75 mg/q.d.) 1 month following percutaneous coronary intervention. Patients were randomly assigned to amlodipine (10 mg p.d., n = 105) or ranolazine (750 mg b.i.d., n = 105) for 15 days, and after a 1-week wash-out period, crossed-over treatment for 15 days. P2Y12 reaction units (PRU) were assessed at baseline and after each treatment sequence. High on-treatment platelet reactivity (HPR) was defined as a PRU > 208. Amlodipine was associated with higher PRU than ranolazine (182 ± 75 vs. 167 ± 64, p = 0.028). As compared with baseline, PRU increased significantly after treatment with amlodipine (p = 0.018), but was not different after ranolazine therapy (p = 0.871). Changes in platelet reactivity following amlodipine therapy appeared to depend on baseline HPR status, as PRU levels significantly increased only among HPR subjects. In stable CAD patients treated with dual antiplatelet therapy after PCI, concomitant treatment with amlodipine, but not ranolazine, interferes with clopidogrel-induced antiplatelet effects.

Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.

Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID.

New Anti-Anginal Drugs: Ranolazine.

Chronic angina represents a condition that impairs quality of life and is associated with decreased life expectancy in the industrialized countries. Current therapies that reduce angina frequency include old drugs such as nitrates, ß -blockers and calcium antagonists. Several new investigational drugs are being tested for the treatment of chronic angina. This review will focus on ranolazine, a drug approved by the US Food and Drug Administration (FDA) in 2006 for patients with chronic angina who continue to be symptomatic despite optimized therapies. The main molecular mechanism underlying ranolazine-mediated beneficial effects has been identified as inhibition of the late Na+ current during the action potential, which potentially improves oxygen consumption, diastolic dysfunction and coronary blood flow. The aim of this review is to update the evidence for ranolazine treatment in chronic angina and discuss its therapeutic perspectives based on the most recent clinical and experimental studies.