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Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects.
- Source :
-
Pharmacotherapy [Pharmacotherapy] 2008 Dec; Vol. 28 (12), pp. 1483-94. - Publication Year :
- 2008
-
Abstract
- Study Objective: To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.<br />Design: Open-label, randomized, crossover, two-arm, parallel-group study.<br />Setting: Single clinical research center in the United Kingdom.<br />Participants: Sixty-nine healthy men aged 18-60 years. Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens.<br />Measurements and Main Results: Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 microM and vasodilator-stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose.<br />Conclusion: Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.
- Subjects :
- Adolescent
Adult
Anticholesteremic Agents adverse effects
Anticholesteremic Agents pharmacology
Area Under Curve
Atorvastatin
Chromatography, Liquid
Clopidogrel
Cross-Over Studies
Dose-Response Relationship, Drug
Drug Interactions
Epistaxis chemically induced
Heptanoic Acids adverse effects
Humans
Liver drug effects
Liver enzymology
Male
Metabolic Clearance Rate drug effects
Middle Aged
Molecular Structure
Piperazines blood
Piperazines chemistry
Platelet Aggregation Inhibitors chemistry
Platelet Aggregation Inhibitors pharmacokinetics
Prasugrel Hydrochloride
Pyrroles adverse effects
Tandem Mass Spectrometry
Thiophenes blood
Thiophenes chemistry
Ticlopidine blood
Ticlopidine chemistry
Ticlopidine pharmacokinetics
United Kingdom
Young Adult
Heptanoic Acids pharmacology
Piperazines pharmacokinetics
Pyrroles pharmacology
Thiophenes pharmacokinetics
Ticlopidine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0277-0008
- Volume :
- 28
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Pharmacotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 19025429
- Full Text :
- https://doi.org/10.1592/phco.28.12.1483