POPULATION PHARMACOKINETICS OF PANTOPRAZOLE IN PATIENTS ON DUAL ANTIPLATELET THERAPY FOLLOWING ACUTE CORONARY SYNDROME

Valentina N. Nikolić, Dragana Stokanović, Slobodan M. Janković, Sandra S. Konstatinović, Jelena B. Zvezdanović, Jelena Lilić, Nikola Stefanović, Svetlana Apostolović, Jasmina R. Milovanović

DOI Number
https://doi.org/10.22190/FUMB240216001N
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Abstract


This study investigates factors influencing pantoprazole pharmacokinetics (PK) in patients with acute coronary syndrome (ACS) undergoing dual antiplatelet therapy (DAPT) comprising acetylsalicylic acid and clopidogrel, alongside concomitant pantoprazole to mitigate gastrointestinal risks. We conducted a prospective analysis on 93 ACS patients, assessing pantoprazole PK parameters and their correlation with C-reactive protein (CRP) levels, indicative of inflammation. Blood samples for pantoprazole concentration and CRP levels were collected according to a predefined schedule, post-oral pantoprazole administration at steady state. The study highlights a notable influence of CRP levels on pantoprazole clearance, underscoring inflammation’s impact on drug metabolism. Elevated CRP was associated with altered pantoprazole pharmacokinetics, suggesting that inflammatory status significantly contributes to metabolic variability in this patient population. Our findings suggest the need for personalized pantoprazole dosing in ACS patients on DAPT, considering the inflammatory status as reflected by CRP levels. This approach could optimize therapeutic efficacy and minimize adverse effects, advancing personalized treatment strategies in the management of ACS.


Keywords

pantoprazole, acute coronary syndrome, population pharmacokinetics, proton pump inhibitors, NONMEM

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Yasuda H, Matsuo Y, Sato Y, et al. Treatment and prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. World J Crit Care Med 2015;4:40-46.

Li JJ, Wu XY, Chen JL, et al. Antiplatelet drug ticagrelor delays gastric ulcer healing in rats. Exp Ther Med 2017;14:3774-3779.

Kheloufi F, Frankel D, Kaspi E, et al. Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis. Therapies 2018;73:273-281.

Jeridi D, Pellat A, Ginestet C, et al. The safety of long-term proton pump inhibitor use on cardiovascular health: a meta-analysis. J Clin Med 2022;11:4096.

Bardou M, Martin J. Pantoprazole: from drug metabolism to clinical relevance. Expert Opin Drug Metab Toxicol 2008;4:471-483.

Andersson T, Holmberg J, Röhss K, et al. Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol 1998;45:369-375.

Hunfeld NG, Touw DJ, Mathot RA, et al. A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism. Aliment Pharmacol Ther 2010;31:150-159.

Gawrońska-Szklarz B, Adamiak-Giera U, Wyska E, et al. CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers. Eur J Clin Pharmacol 2012;68:1267-1274.

El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol 2018;14:447-460.

Stanke-Labesque F, Gautier-Veyret E, Chhun S, et al. Inflammation is a major regulator of drug metabolizing enzymes and transporters: consequences for the personalization of drug treatment. Pharmacol Ther 2020;215:107627.

Klein M, Thomas M, Hofmann U, et al. A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells. Drug Metab Dispos 2015;43:273-283.

Dickmann LJ, Patel SK, Rock DA, et al. Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos 2011;39:1415–1422.

Simon F, Gautier-Veyret E, Truffot A, et al. Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates. Pharm Res 2021;38:415-428.

Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–454.

Klomp SD, Manson ML, Guchelaar HJ, et al. Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review. J Clin Med 2020;9:2890.

Mostafa S, Kirkpatrick CMJ, Byron K, et al. An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. J Neural Transm 2019;126:5-18.

Meyer UA. Interaction of proton pump inhibitors with cytochromes P450: consequences for drug interactions. Yale J Biol Med 1996;69:203-209.

Willrich MA, Hirata MH, Hirata RD. Statin regulation of CYP3A4 and CYP3A5 expression. Pharmacogenomics 2009;10:1017-1024.

Watanabe M, Kumai T, Matsumoto N, et al. Expression of CYP3A4 mRNA is correlated with CYP3A4 protein level and metabolic activity in human liver. J Pharmacol Sci. 2004;94:459-462.

Kunze A, Poller B, Huwyler J, Camenisch G. Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins. Drug Metab Pers Ther. 2015 Sep;30(3):175-88.




DOI: https://doi.org/10.22190/FUMB240216001N

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