Effect of Atorvastatin and Clopidogrel in Healthy Subjects
Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.
Design. Open-label, randomized, crossover, two-arm, parallel-group study.
Setting. Single clinical research center in the United Kingdom.
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.
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 µM 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.
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.
Prasugrel and clopidogrel are thienopyridine antiplatelet agents that inhibit adenosine-5'diphosphate (ADP)–induced platelet aggregation. As prodrugs, thienopyridines require metabolic conversion to the pharmaco-logically active compounds. These active metabolites contain a thiol group that forms an irreversible disulfide bond with cysteine(s) on platelet P2Y12 purinergic (P-2) ADP receptors, leading to inhibition of platelet activation and aggregation. Once exposed, platelets are affected for their life span of approximately 7–10 days.
Dual antiplatelet therapy with aspirin and clopidogrel are standard of care for the treatment or prevention of ischemic events in individuals with acute coronary syndromes who are undergoing percutaneous coronary intervention. Prasugrel is a novel thienopyridine under development, and clinical studies have demonstrated that a prasugrel 60-mg loading dose rapidly produces greater inhibition of ADP-induced platelet aggregation compared with a 300-or 600-mg loading dose of clopidogrel. The increased platelet inhibitory potency of prasugrel relative to clopidogrel arises from more efficient conversion of the prodrug to its active metabolite. Carboxylesterases rapidly convert prasugrel to a thiolactone intermediate, which is converted to the active metabolite by cytochrome P450 (CYP) isoforms CYP3A4/5, CYP2B6, CYP2C9 and/or CYP2C19 (Figure 1). The active metabolite of prasugrel is metabolized by S-methylation to R-106583 and by conjugation with cysteine to R-119251. In contrast, formation of clopidogrel's active metabolite requires two sequential CYP-mediated enzymatic steps. In a competing reaction, esterases convert clopidogrel to inactive metabolites, with about 85% of an administered clopidogrel dose entering this hydrolytic pathway.
(Enlarge Image)
Figure 1.
Metabolic pathways for prasugrel, clopidogrel, and their respective metabolites.
The CYP3A subfamily of CYP enzymes appears to play an important role in the conversion of the thienopyridines to their respective active metabolites. Inhibition of CYP3A activity can affect the pharmacokinetics of drugs that are CYP3A4 substrates and may lead to clinically relevant alterations in efficacy, safety, and/or pharmacodynamic response to the substrate drug. In a recent study, ketoconazole, a potent CYP3A4/5 inhibitor, significantly reduced exposure to clopidogrel's active metabolite, resulting in decreased inhibition of platelet aggregation (IPA), after concomitant loading and maintenance dosing with clopidogrel. In the same study, ketoconazole significantly reduced the maximum plasma concentration (Cmax), but not the area under the plasma concentration–time curve (AUC), for prasugrel's active metabolite, and did not affect the pharmacodynamic response to prasugrel as measured by inhibition of ADP-induced platelet aggregation.
Although a substrate for an enzyme may also act as an inhibitor, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) metabolized by CYP3A, such as atorvastatin, lovastatin, and simvastatin, have not been reported to be inhibitors of the enzyme. In a small study (≤ 7 patients/dose group), atorvastatin—but not pravastatin, which is not metabolized by CYP3A—was reported to have dose dependently decreased IPA by clopidogrel in patients with stents who concomitantly received a statin. Another study also demonstrated a negative effect of atorvastatin on clopidogrel pharmacodynamics with use of P-selectin, a marker of platelet activation. In contrast, several other reports found no evidence of a statin-clopidogrel drug-drug interaction using both biomarkers as end points or analyses of outcomes in clinical trials.
We conducted this study to assess the potential for an interaction between atorvastatin and the thienopyridines prasugrel and clopidogrel since patients with cardiovascular disease are likely to take a thienopyridine antiplatelet agent concomitantly with a statin. The hypothesis was that such an interaction would not occur with prasugrel based on results of the previous prasugrel and ketoconazole drug interaction study and on in vitro metabolism studies with prasugrel. To our knowledge, our study is the first prospective, statistically powered pharmacokinetic study to address uncertainty regarding a drug-drug interaction between clopidogrel and lipophilic statins, as well as the first study in which the plasma concentrations of clopidogrel's active metabolite were measured by a validated analytic method while simultaneously measuring the pharmacodynamic response to clopidogrel when given with and without atorvastatin. Moreover, since potent inhibition of CYP3A affected the pharmacokinetics of and pharmacodynamic response to prasugrel and clopidogrel differently, it was of interest to investigate whether such differences occurred after coadministration of a CYP3A substrate (i.e., atorvastatin) with each thienopyridine.
Abstract and Introduction
Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.
Design. Open-label, randomized, crossover, two-arm, parallel-group study.
Setting. Single clinical research center in the United Kingdom.
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.
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 µM 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.
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.
Introduction
Prasugrel and clopidogrel are thienopyridine antiplatelet agents that inhibit adenosine-5'diphosphate (ADP)–induced platelet aggregation. As prodrugs, thienopyridines require metabolic conversion to the pharmaco-logically active compounds. These active metabolites contain a thiol group that forms an irreversible disulfide bond with cysteine(s) on platelet P2Y12 purinergic (P-2) ADP receptors, leading to inhibition of platelet activation and aggregation. Once exposed, platelets are affected for their life span of approximately 7–10 days.
Dual antiplatelet therapy with aspirin and clopidogrel are standard of care for the treatment or prevention of ischemic events in individuals with acute coronary syndromes who are undergoing percutaneous coronary intervention. Prasugrel is a novel thienopyridine under development, and clinical studies have demonstrated that a prasugrel 60-mg loading dose rapidly produces greater inhibition of ADP-induced platelet aggregation compared with a 300-or 600-mg loading dose of clopidogrel. The increased platelet inhibitory potency of prasugrel relative to clopidogrel arises from more efficient conversion of the prodrug to its active metabolite. Carboxylesterases rapidly convert prasugrel to a thiolactone intermediate, which is converted to the active metabolite by cytochrome P450 (CYP) isoforms CYP3A4/5, CYP2B6, CYP2C9 and/or CYP2C19 (Figure 1). The active metabolite of prasugrel is metabolized by S-methylation to R-106583 and by conjugation with cysteine to R-119251. In contrast, formation of clopidogrel's active metabolite requires two sequential CYP-mediated enzymatic steps. In a competing reaction, esterases convert clopidogrel to inactive metabolites, with about 85% of an administered clopidogrel dose entering this hydrolytic pathway.
(Enlarge Image)
Figure 1.
Metabolic pathways for prasugrel, clopidogrel, and their respective metabolites.
The CYP3A subfamily of CYP enzymes appears to play an important role in the conversion of the thienopyridines to their respective active metabolites. Inhibition of CYP3A activity can affect the pharmacokinetics of drugs that are CYP3A4 substrates and may lead to clinically relevant alterations in efficacy, safety, and/or pharmacodynamic response to the substrate drug. In a recent study, ketoconazole, a potent CYP3A4/5 inhibitor, significantly reduced exposure to clopidogrel's active metabolite, resulting in decreased inhibition of platelet aggregation (IPA), after concomitant loading and maintenance dosing with clopidogrel. In the same study, ketoconazole significantly reduced the maximum plasma concentration (Cmax), but not the area under the plasma concentration–time curve (AUC), for prasugrel's active metabolite, and did not affect the pharmacodynamic response to prasugrel as measured by inhibition of ADP-induced platelet aggregation.
Although a substrate for an enzyme may also act as an inhibitor, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) metabolized by CYP3A, such as atorvastatin, lovastatin, and simvastatin, have not been reported to be inhibitors of the enzyme. In a small study (≤ 7 patients/dose group), atorvastatin—but not pravastatin, which is not metabolized by CYP3A—was reported to have dose dependently decreased IPA by clopidogrel in patients with stents who concomitantly received a statin. Another study also demonstrated a negative effect of atorvastatin on clopidogrel pharmacodynamics with use of P-selectin, a marker of platelet activation. In contrast, several other reports found no evidence of a statin-clopidogrel drug-drug interaction using both biomarkers as end points or analyses of outcomes in clinical trials.
We conducted this study to assess the potential for an interaction between atorvastatin and the thienopyridines prasugrel and clopidogrel since patients with cardiovascular disease are likely to take a thienopyridine antiplatelet agent concomitantly with a statin. The hypothesis was that such an interaction would not occur with prasugrel based on results of the previous prasugrel and ketoconazole drug interaction study and on in vitro metabolism studies with prasugrel. To our knowledge, our study is the first prospective, statistically powered pharmacokinetic study to address uncertainty regarding a drug-drug interaction between clopidogrel and lipophilic statins, as well as the first study in which the plasma concentrations of clopidogrel's active metabolite were measured by a validated analytic method while simultaneously measuring the pharmacodynamic response to clopidogrel when given with and without atorvastatin. Moreover, since potent inhibition of CYP3A affected the pharmacokinetics of and pharmacodynamic response to prasugrel and clopidogrel differently, it was of interest to investigate whether such differences occurred after coadministration of a CYP3A substrate (i.e., atorvastatin) with each thienopyridine.
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