Studies to Investigate the Pharmacokinetic Interactions Between Ranolazine and Ketoconazole, Diltiazem, or Simvastatin During Combined Administration in Healthy Subjects

Abstract

The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

“…17 The metabolite to ranolazine area under the curve from time 0 to 12 hours (AUC 12 ) ratio decreased 5.6-fold, 2.1-fold, and 4.6-fold for CVT-2512, CVT-2514, and CVT 2738, respectively. Adverse events, generally mild to moderate, but occasionally intolerable, such as headache, dizziness, and nausea, are significantly increased with the concomitant administration of ketoconazole 200 mg twice daily to ranolazine 1000 mg twice daily.…”

The Relationship between the Drug Concentration Profiles in Plasma and the Drug Doses in the Colon

“…It has been shown that diltiazem caused clinically significant drug-drug interactions by decreasing the elimination of substrates through the inhibition of CYP3A. 39,40) The cause of inhibition has been attributed to both diltiazem and its metabolites. Therefore, at high doses, CYP3A-mediated firstpass metabolism of diltiazem in the intestine and/or liver may be inhibited and/or saturated by itself and its metabolites.…”

Advances in the Management of Stable Angina

“…15 Diltiazem 180 mg/day and 360 mg/day increased steady-state plasma ranolazine concentrations 1.8-fold and 2.3-fold, respectively, when diltiazem was used concomitantly with ranolazine 1,000 mg twice daily. 1,15 Less potent CYP3A4…”

“…1,15 Ketoconazole 200 mg twice daily increased average plasma ranolazine concentrations more than 3-fold when it was administered concurrently with extended-release ranolazine 1,000 mg twice daily. 15 Diltiazem 180 mg/day and 360 mg/day increased steady-state plasma ranolazine concentrations 1.8-fold and 2.3-fold, respectively, when diltiazem was used concomitantly with ranolazine 1,000 mg twice daily. 1,15 Less potent CYP3A4…”