Abstract
Aim:
To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects.
Methods:
This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay.
Results:
Thirty-six healthy native Chinese subjects (19 males) aged 18–45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC0–4 and Cmax increased dose-proportionally across the dose range of 5 mg to 60 mg. The median Tmax was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%–98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87%–90%) and was lower in the 7.5 mg and 5 mg MD groups (79%–83% and 64%–67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d.
Conclusion:
The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Baker WL, White CM . Role of prasugrel, a novel P2Y12 receptor antagonist, in the management of acute coronary syndromes. Am J Cardiovasc Drugs 2009; 9: 213–29.
Niitsu Y, Jakubowski JA, Sugidachi A, Asai F . Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost 2005; 31: 184–94.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15.
Ernest CS II, Small DS, Rohatagi S, Salazar DE, Wallentin L, Winters KJ, et al. Population pharmacokinetics and pharamcodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn 2008; 35: 593–618.
Small DS, Payne CD, Kothare P, Yuen E, Natanegara F, Teng Loh M, et al. Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: an open-label trial. Clin Ther 2010; 32: 365–79.
Small DS, Kothare P, Yuen E, Lachno DR, Li YG, Winters KJ, et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol 2010; 66: 127–35.
Small DS, Li YG, Ernest CS II, April JH, Farid NA, Payne CD, et al. Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent. J Clin Pharmacol 2011; 51: 321–32.
Farid NA, McIntosh M, Garofolo F, Wong E, Shwajch A, Kennedy M, et al. Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007; 21: 169–79.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res 2000; 17: 1278–83.
Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS II, et al. Common polymorphism of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429–36.
Acknowledgements
The study was financially supported by Eli Lilly and Company, Indianapolis, Indiana, USA. The authors are indebted to the patients who participated in this study and their families and to all of the physicians, nurses, and study coordinators who cared for the patients. The authors acknowledge the following persons for their assistance in the study and the development of the manuscript: Pei-hong SUN, Yan LIANG, Dong-mei ZHANG and Jing-zi LI.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cui, Ym., Wang, Zn., Chen, Xw. et al. Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects. Acta Pharmacol Sin 33, 1395–1400 (2012). https://doi.org/10.1038/aps.2012.120
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2012.120
Keywords
This article is cited by
-
Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans
Acta Pharmacologica Sinica (2021)
-
Hormonal, chemical and thermal inhibition of spermatogenesis: contribution of French teams to international data with the aim of developing male contraception in France
Basic and Clinical Andrology (2017)
-
World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI
Nature Reviews Cardiology (2014)
-
Pharmacometrics: a quantitative tool of pharmacological research
Acta Pharmacologica Sinica (2012)