Valentina Nikolić, Slobodan M. Janković, Dragana Stokanović, Sandra S. Konstantinović, Jelena B. Zvezdanović, Nikola Stefanović, Jelena Lilić, Svetlana R. Apostolović, Tatjana Jevtović-Stoimenov, Jasmina R. Milovanović

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The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies.


2-oxo-clopidogrel, acute coronary syndrome, population pharmacokinetics, clearance, Nonlinear mixed effects model (NONMEM).

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Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49:2312–2317.

Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48:1742–1750.

Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53:849–856.

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015.

Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29:21−30.

Karaźniewicz-Łada M, Danielak D, Burchardt P, Kruszyna L, Komosa A, Lesiak M, Główka F. Clinical pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. Clin Pharmacokinet 2014; 53:155−164.

Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92−99. doi:10.1124/dmd.109.029132.

Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N, et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 2004; 92: 311−316. her 84, 236−242.

Elsinghorst PW. Quantitative determination of clopidogrel and its metabolites in biological samples: a mini-review. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 917–918: 48–52.

Li X, Liu C, Zhu X, Wei H, et al. Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers. Front Pharmacol 2018; 9:643. doi: 10.3389/fphar.2018.00643. eCollection 2018.

Beal SL, Boeckmann AJ, Sheiner LB. NONMEM users guide. Parts I–VIII ICON Development Solutions 2013. Ellicott City, MD, USA.

Milovanovic JR, Jankovic SM. Population pharmacokinetics of lamotrigine in patients with epilepsy. Int J Clin Pharmacol Ther 2009; 47:752–760.

FDA (1999). Guidance for Industry Population Pharmacokinetics. FDA, Rockville. Available at: https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf (Last assessed: 10.12.2018.)

Yousef AM, Melhem M, Xue B, Arafat T, Reynolds DK, Van Wart SA. Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy. Biopharm Drug Dispos 2013; 34(4):215–226. doi:10.1002/bdd.1839.

Lee J, Hwang Y, Kang W, et al. Population pharmacokinetic/

pharmacodynamic modeling of clopidogrel in Korean healthy volunteers and stroke patients. J Clin Pharmacol 2012; 52(7):985–995. doi:10.1177/0091270011409228

Danielak D, Karaźniewicz-Łada M, Komosa A, Burchardt P, Lesiak M, Kruszyna Ł, Graczyk-Szuster A, Główka F. Influence of genetic co-factors on the population pharmacokinetic model for clopidogrel and its active thiol metabolite. Eur J Clin Pharmacol 2017; 73(12):1623–1632. doi: 10.1007/s00228-017-2334-z.

Peeters PA, Crijns HJ, Tamminga WJ, Jonkman JH, Dickinson JP, Necciari J. Clopidogrel, a novel antiplatelet agent, and digoxin: absence of pharmacodynamic and pharmacokinetic interaction. Semin Thromb Hemost 1999; 25 Suppl 2:51–54.

Van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veld-huisen DJ, Voors AA. Abnormal liver function in relation to hemodynamic profile in heart failure patients. J Card Fail 2010; 16:84–90.

DOI: https://doi.org/10.22190/FUMB181224015N


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