Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects

The interactions of ranolazine, anew antianginal compound, with inhibitors and substrates of the GYP3A 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 phormaco-kinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvostatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvostatin metabolites, and HMG-CoA reductuse activity. Ketoconazole increosed ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformotion of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranoluzine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvustatin 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.