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

J Clin Pharmacol. 2005 Apr;45(4):422-33. doi: 10.1177/0091270004273992.


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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Acetanilides
  • Adolescent
  • Adult
  • Diltiazem / chemistry
  • Diltiazem / pharmacokinetics*
  • Double-Blind Method
  • Drug Combinations
  • Drug Interactions / physiology
  • Female
  • Humans
  • Ketoconazole / chemistry
  • Ketoconazole / pharmacokinetics*
  • Male
  • Middle Aged
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics*
  • Ranolazine
  • Simvastatin / chemistry
  • Simvastatin / pharmacokinetics*


  • Acetanilides
  • Drug Combinations
  • Piperazines
  • Ranolazine
  • Simvastatin
  • Diltiazem
  • Ketoconazole