Transl Clin Pharmacol.  2017 Dec;25(4):202-208. 10.12793/tcp.2017.25.4.202.

Pharmacokinetic drug interaction between atorvastatin and ezetimibe in healthy Korean volunteers

Affiliations
  • 1Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
  • 2Departmenrt of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. tghong@yuhs.ac
  • 3Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
  • 4Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Abstract

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (C(max,ss)) and the area under the curve within a dosing interval at steady state (AUC(Ï„,ss)) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799-1.2544) and 1.1154 (1.0079-1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227-1.0849) and 1.0176 (0.9465-1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.

Keyword

Atorvastatin; Ezetimibe; Pharmacokinetics; Drug interaction

MeSH Terms

Atorvastatin Calcium*
Cholesterol
Cross-Over Studies
Drug Interactions*
Dyslipidemias
Ezetimibe*
Humans
Lipoproteins
Male
Pharmacokinetics
Plasma
Volunteers*
Atorvastatin Calcium
Cholesterol
Ezetimibe
Lipoproteins

Figure

  • Figure 1 Study design; treatment A, atorvastatin 40 mg once daily for seven days; treatment B, ezetimibe 10 mg once daily for seven days; treatment C, co-administration of atorvastatin 40 mg and ezetimibe 10 mg once daily for seven days.

  • Figure 2 Plasma concentration-time profiles of atorvastatin with or without ezetimibe at steady state plotted using (a) linear and (b) log-linear scales, and of 2-hydroxyatorvastatin (c) linear and (d) log-linear scales.

  • Figure 3 Plasma concentration-time profiles of total ezetimibe with or without atorvastatin at steady state plotted using (a) linear and (b) log-linear scales, and of free ezetimibe (c) linear and (d) log-linear scales.


Reference

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143–3421. PMID: 12485966.
2. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(Suppl2):S1–S45. DOI: 10.1161/01.cir.0000437738.63853.7a. PMID: 24222016.
3. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American association of clinical endocrinologists and American college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017; 23:479–497. DOI: 10.4158/EP171764.GL. PMID: 28156151.
Article
4. Ito MK. Dyslipidemia: management using optimal lipid-lowering therapy. Ann Pharmacother. 2012; 46:1368–1381. DOI: 10.1345/aph.1R127. PMID: 23032652.
Article
5. Ewang-Emukowhate M, Wierzbicki AS. Lipid-lowering agents. J Cardiovasc Pharmacol Ther. 2013; 18:401–411. DOI: 10.1177/1074248413492906. PMID: 23811423.
Article
6. Malhotra HS, Goa KL. Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia. Drugs. 2001; 61:1835–1881. PMID: 11693468.
7. Patel SB. Ezetimibe: a novel cholesterol-lowering agent that highlights novel physiologic pathways. Curr Cardiol Rep. 2004; 6:439–442. PMID: 15485605.
Article
8. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005; 44:467–494. PMID: 15871634.
9. Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, et al. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40 mg) Compared With Uptitration of Atorvastatin (to 80 mg) in Hypercholesterolemic Patients at High Risk of Coronary Heart Disease. Am J Cardiol. 2008; 102:1495–1501. DOI: 10.1016/j.amjcard.2008.09.076. PMID: 19026303.
Article
10. Bardini G, Giorda CB, Pontiroli AE, Le Grazie C, Rotella CM. Ezetimibe + simvastatin versus doubling the dose of simvastatin in high cardiovascular risk diabetics: a multicenter, randomized trial (the LEAD study). Cardiovasc Diabetol. 2010; 9:20. DOI: 10.1186/1475-2840-9-20. PMID: 20492655.
Article
11. Zhu Y, Statkevich P, Kosoglou T, Maxwell S, Anderson L, Patrick J, et al. Piii-15 Lack Of A Pharmacokinetic Interaction Between Ezetimibe And Atorvastatin. Clin Pharmacol Ther. 2001; 69:P68.
12. Patiño-Rodríguez O, Torres-Roque I, Martínez-Delgado M, Escobedo-Moratilla A, Pérez-Urizar J. Pharmacokinetic non-interaction analysis in a fixed-dose formulation in combination of atorvastatin and ezetimibe. Front Pharmacol. 2014; 5:261. DOI: 10.3389/fphar.2014.00261. PMID: 25505887.
Article
13. Nardi R, Masina M, Cioni G, Leandri P, Zuccheri P. Generic-equivalent drugs use in internal and general medicine patients: distrust, confusion, lack of certainties or of knowledge? Part 3. Clinical issues. Italian J Med. 2014; 8:99–109.
14. Kosoglou T, Statkevich P, Fruchart JC, Pember LJ, Reyderman L, Cutler DL, et al. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin. 2004; 20:1197–1207. PMID: 15324522.
Article
15. Min KL, Park MS, Jung J, Chang MJ, Kim CO. Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects. Clin Ther. 2017; 39:1799–1810. DOI: 10.1016/j.clinthera.2017.07.038. PMID: 28803122.
Article
16. Min KL, Park MS, Jung J, Chang MJ, Kim CO. Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects. Clin Ther. 2017; 39:1799–1810. DOI: 10.1016/j.clinthera.2017.07.038. PMID: 28803122.
Article
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