Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects.
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.
Jerling
Markus
M
CV Therapeutics Inc, 3172 Porter Drive, Palo Alto, CA 94304, USA.
Huan
Bee-Lian
BL
Leung
Kwan
K
Chu
Nancy
N
Abdallah
Hisham
H
Hussein
Ziad
Z
D000083:Acetanilides; D000293:Adolescent; D000328:Adult; D004110:Diltiazem / Q000737:chemistry / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics*; D000069458:Ranolazine; D019821:Simvastatin / Q000737:chemistry / Q000493:pharmacokinetics*
D000083:Acetanilides; D004338:Drug Combinations; D010879:Piperazines; D000069458:Ranolazine; D019821:Simvastatin; D004110:Diltiazem; D007654:Ketoconazole