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Pharmacokinetic Drug Interaction Between Atorvastatin and Ezetimibe

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Pharmacokinetic Drug Interaction Between Atorvastatin and Ezetimibe 2017;25(4):202-208 TCP Transl Clin Pharmacol http://dx.doi.org/10.12793/tcp.2017.25.4.202 Pharmacokinetic drug interaction between atorvastatin and ezetimibe in healthy Korean volunteers Jungsin Park1, Choon Ok Kim2, Byung Hak Jin1,2, Seoungwon Yang3, Min Soo Park1,2,4 and Taegon Hong2* 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, Repub- lic of Korea, 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 ORIGINAL ARTICLE *Correspondence: T. G. Hong; Tel: 82-2-2228-0465, Fax: 82-2-2227-7890, E-mail: [email protected] Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for Received 11 Nov 2017 the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug Revised 11 Dec 2017 interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The Accepted 11 Dec 2017 aim of this study was to investigate PK drug interaction between two drugs in healthy Korean vol- Keywords unteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design Atorvastatin, crossover study was conducted in 36 healthy male subjects. During each period, the subjects re- Ezetimibe, Pharmacokinetics, ceived one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or Drug interaction a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of pISSN: 2289-0882 atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and eISSN: 2383-5427 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 (Cmax,ss) and the area under the curve within a dosing interval at steady state (AUCτ,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 ezeti- mibe showed similar PK and safety profile compared with each drug alone. The PK interaction -be tween two drugs was not clinically significant in healthy Korean volunteers. Introduction III of the National Cholesterol Education Program and 2013 Dyslipidemia refers to elevated total or low-density lipoprotein guidelines of the American College of Cardiology (ACC)/ (LDL) cholesterol levels, or reduced high-density lipoprotein American Heart Association (AHA), decreasing blood LDL (HDL) cholesterol level due to impaired lipoprotein metabo- cholesterol is key to the management of dyslipidemia.[1,2] The lism. According to the guidelines of the Adult Treatment Panel treatment of dyslipidemia includes therapeutic lifestyle changes, such as weight management, limited intake of saturated fats and Copyright © 2017 Translational and Clinical Pharmacology cholesterol, and drug therapy. Aggressive actions to reduce LDL It is identical to the Creative Commons Attribution Non-Commercial License cholesterol are recommended for patients at a higher risk of de- (http://creativecommons.org/licenses/by-nc/3.0/). This paper meets the requirement of KS X ISO 9706, ISO 9706-1994 and veloping cardiovascular disease (CVD).[3,4] ANSI/NISO Z.39.48-1992 (Permanence of Paper). Statins are currently used as first-line therapy for dyslipidemia because they have clear prognostic benefits, such as decreasing Reviewer CVD incidence and increasing survival rate by lowering LDL This article was reviewed by peer experts who are not TCP editors. cholesterol, with relatively low side effects.[5] Atorvastatin is 202 Vol. 25, No.4, Dec 15, 2017 Jungsin Park, et al. TranslTCP Clin Pharmacol a well-known statin that inhibits cholesterol synthesis in the 1). The IPs were atorvastatin calcium (40 mg, Lipitor®, Pfizer liver by competitively inhibiting 3-hydroxy-3-methylglutaryl Korea Ltd.) and ezetimibe (10 mg, Ezetrol®, MSD Korea Ltd.). coenzyme A reductase.[6] However, additional measures are All subjects were randomly assigned to one of the following necessary when aggressive statin therapy does not adequately six treatment sequences: ABC, ACB, BCA, BAC, CAB, or CBA decrease LDL cholesterol or when statin therapy is discontin- with an 11-day washout period between treatments A, B, and ued due to side effects. In such cases, the ACC/AHA guidelines C. The treatment regimens were once daily administrations of recommend the use of a combination of low-dose statin and atorvastatin 40 mg (treatment A), ezetimibe 10 mg (treatment another non-statin lipid-modifying agent.[2] B), or co-administration of atorvastatin 40 mg and ezetimibe 10 Ezetimibe is a lipid-modifying agent that inhibits the absorp- mg (treatment C) for seven days. The subjects visited the outpa- tion of cholesterol present in food or bile by blocking the Nie- tient clinic at 8 am each morning, and were orally administered mann–Pick C1-like 1 protein in the villi of the small intestine. the assigned IP with 240 mL water at the fasted state for the first [7,8] A previous study, which investigated patients with CVD or six days of each period (D1~D6, D18~D23, and D35~D40). diabetes, found that ezetimibe-statin combination therapy was They were hospitalized in the afternoon on the 6th day of each more effective than monotherapy with a high-dose statin at low- period for intensive PK sampling and safety assessment. After ering LDL cholesterol and other lipid parameters.[9,10] Owing overnight fasting, the 7th dose of the IP was orally administered to such synergistic advantages and low side effects, ezetimibe with 240 mL water; all subjects were prohibited from drinking is frequently co-administered with statins in clinical practice. water for 1 h before and after IP administration. After fasting Further, it is necessary to develop a fixed-dose combination to for 4 h post-dose, a standard meal (700–800 kcal and 5–25% fat) improve medication compliance; however, the pharmacokinetic was served to all subjects at 4 and 10 h after dosing. (PK) drug interaction between atorvastatin and ezetimibe in Korean population has not been evaluated. Therefore, this study Blood Sampling and Determination of Drug Concentra- was conducted to investigate the PK interaction between ator- tions vastatin 40 mg and ezetimibe 10 mg in healthy Korean volun- Serial blood samples were collected in heparinized tubes at 0 teers. (pre-dose), 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 h after the last IP administration in each period. Methods Blood samples were also collected to estimate trough plasma This study was conducted at the Clinical Trials Center, Yonsei concentration at 0 h (pre-dose) before the 5th and the 6th doses. University Severance Hospital (Seoul, Korea) in accordance For treatment groups B and C, blood samples were additionally with the Declaration of Helsinki and the guidelines of the Ko- collected at 72 and 96 h after the last dosing for the determina- rean Good Clinical Practices after approval of the protocol by tion of ezetimibe concentrations. The samples were centrifuged the Institutional Review Board of Severance Hospital (approval (1,800 g, 4˚C, 10 min), and the supernatants were separated and number: 4-2014-0742). The study was registered at ClinicalTri- stored at -70˚C until the analysis of drug concentrations. als.gov with the identifier number NCT02288338. All subjects Plasma concentrations of atorvastatin, 2-hydroxyatorvastatin, fully understood the objectives, procedures, risks, and benefits total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and of the study before providing their written informed consents prior to enrollment. Subjects Healthy Korean volunteers aged 19–45 years with body mass index (BMI) of 18.5–25 kg/m2 and weight > 55 (for males) or > 50 kg (for females) were screened for enrollment based on medical history, physical examination, and the results of clinical laboratory tests (hematology, blood chemistry, serologic test, urinalysis, and urine drug test). Subjects with a history of gas- trointestinal disease or surgery that could affect the absorption of the investigational products (IPs) or those allergic to the IPs were excluded. Additionally, subjects with a history of genetic disorders, such as galactose intolerance or Lapp lactase defi- ciency, were excluded. Figure 1. Study design; treatment A, atorvastatin 40 mg once daily for Study Design and Procedures seven days; treatment B, ezetimibe 10 mg once daily for seven days; This was a randomized, open-label, multiple-dose, three- treatment C, co-administration of atorvastatin 40 mg and ezetimibe 10 treatment, three-period, Williams design crossover study (Fig. mg once daily for seven days. 203 Vol. 25, No.4, Dec 15, 2017 Atorvastatin and ezetimibe interaction TCPTransl Clin Pharmacol free ezetimibe were measured by liquid chromatography (Shi- (ECG) throughout the study. All AEs reported by the subjects
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