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

Journal of Clinical Pharmacology

Volumn 45, Issue 4, 2005, Pages 422-433

  Jerling, Markus ^a   Huan, Bee Lian ^a   Leung, Kwan ^a   Chu, Nancy ^a   Abdallah, Hisham ^a   Hussein, Ziad ^b  

^a CV THERAPEUTICS INC   (United States)

^b Medeval Ltd   (United Kingdom)

Author keywords

Diltiazem; Drug interactions; Ketoconazole; Ranolazine; Simvastatin

Indexed keywords

ANTIANGINA PECTORIS AGENT; ANTIFUNGAL AGENT; CALCIUM CHANNEL BLOCKING AGENT; CYTOCHROME P450 3A4; DILTIAZEM; DRUG METABOLITE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; KETOCONAZOLE; LACTONE; PLACEBO; RANOLAZINE; SIMVASTATIN;

ADULT; AREA UNDER THE CURVE; ARTICLE; ATRIOVENTRICULAR BLOCK; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIZZINESS; DOSE TIME EFFECT RELATION; DRUG BLOOD LEVEL; DRUG CAPSULE; DRUG CLEARANCE; DRUG METABOLISM; DRUG SAFETY; FEMALE; HUMAN; HUMAN EXPERIMENT; LIVER TOXICITY; MALE; NAUSEA; NORMAL HUMAN; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; STEADY STATE; TABLET; THORAX PAIN; VISUAL DISORDER;

ADOLESCENT; ADULT; DILTIAZEM; DOUBLE-BLIND METHOD; DRUG COMBINATIONS; DRUG INTERACTIONS; FEMALE; HUMANS; KETOCONAZOLE; MALE; MIDDLE AGED; PIPERAZINES; SIMVASTATIN;

EID: 16844369128     PISSN: 00912700     EISSN: None     Source Type: Journal    
DOI: 10.1177/0091270004273992     Document Type: Article

References (21)

1. Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol. 1999;84:46-50.
2. Zacharowski K, Blackburn B, Thiemermann C. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol. 2001;418:105-110.
3. 14C]- ranolazine in humans [abstract 98]. Drug Metab Rev. 2003;35:49.
4. Chu N, Soohoo D, Sun H-L, et al. In vitro metabolism of ranolazine [abstract 363]. Drug Metab Rev. 2003;35:182.
5. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41-57.
6. Gomez DY, Wacher VJ, Tomlanovich SJ, Hebert MF, Benet LZ. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther. 1995;58:15-19.
7. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA. 1993;269:1513-1518.
8. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55:481-485.
9. von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther. 1996;276:370-379.
10. Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther. 1997;282:294-300.
11. Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, Hall SD. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther. 1999;290:1116-1125.
12. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther. 1998;63:332-341.
13. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67:267-274.
14. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol. 1999;48:610-615.
15. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177-182.
16. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther. 1998;64:477-483.
17. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993;24:195-202.
18. Zhao H, Chow MS. Analysis of diltiazem and desacetyldiltiazem in plasma using modified high-performance liquid chromatography: improved sensitivity and reproducibility. Pharm Res. 1989;6:428-430.
19. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol. 1998;38:389-430.
20. Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf. 2000;22:441-457.
21. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol. 1999;84:811-815.