Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects.
OBJECTIVE
To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.


METHODS
Open-label, randomized, crossover, two-arm, parallel-group study.


METHODS
Single clinical research center in the United Kingdom.


METHODS
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.


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.


CONCLUSIONS
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.
Farid
Nagy A
NA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. nafarid@lilly.com
Small
David S
DS
Payne
Christopher D
CD
Jakubowski
Joseph A
JA
Brandt
John T
JT
Li
Ying G
YG
Ernest
C Steven
CS
Salazar
Daniel E
DE
Konkoy
Christopher S
CS
Winters
Kenneth J
KJ
D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D000069059:Atorvastatin; D002853:Chromatography, Liquid; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004844:Epistaxis / Q000139:chemically induced; D006538:Heptanoic Acids / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D015394:Molecular Structure; D010879:Piperazines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D000068799:Prasugrel Hydrochloride; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D006113:United Kingdom; D055815:Young Adult
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D013876:Thiophenes; D000069059:Atorvastatin; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine