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Hydrochlorothiazide 60/10/25 Mg and a Corresponding Loose Combination of Fimasartan/Amlodipine 60/25 Mg and Hydrochlorothiazide 25 Mg in Healthy Subjects

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Hydrochlorothiazide 60/10/25 Mg and a Corresponding Loose Combination of Fimasartan/Amlodipine 60/25 Mg and Hydrochlorothiazide 25 Mg in Healthy Subjects Transl Clin Pharmacol. 2021 Mar;29(1):53-64 https://doi.org/10.12793/tcp.2021.29.e5 pISSN 2289-0882·eISSN 2383-5427 Original Article Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects Received: Jan 12, 2021 1 1 1 1 Revised: Mar 14, 2021 Jihyun Jung , Soyoung Lee , Jaeseong Oh , SeungHwan Lee , Accepted: Mar 16, 2021 In-Jin Jang 1, Donghwan Lee 2, and Kyung-Sang Yu 1,* *Correspondence to 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Kyung-Sang Yu Hospital, Seoul 03080, Korea Department of Clinical Pharmacology and 2Department of Statistics, Ewha Womans University, Seoul 03760, Korea Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak- ro, Jongno-gu, Seoul 03080, Korea. E-mail: [email protected] ABSTRACT Copyright © 2021 Translational and Clinical For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive Pharmacology drugs can provide complementary benefits from improved compliance and cost-effectiveness It is identical to the Creative Commons Attribution Non-Commercial License (https:// compared with loose combinations of corresponding drugs. A new FDC of fimasartan/ creativecommons.org/licenses/by-nc/4.0/). amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover ORCID iDs phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC Jihyun Jung of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of https://orcid.org/0000-0002-8904-3212 Soyoung Lee a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 https://orcid.org/0000-0001-5799-4489 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial Jaeseong Oh blood samples were collected, and plasma concentrations of fimasartan, amlodipine and https://orcid.org/0000-0001-6275-8587 hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC SeungHwan Lee were similar to those of the loose combinations. The geometric mean ratios (GMRs) and https://orcid.org/0000-0002-1713-9194 In-Jin Jang 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma https://orcid.org/0000-0002-8384-3139 concentration (Cmax) and area under the curve until the last measurable time point (AUClast) Donghwan Lee were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs https://orcid.org/0000-0002-3878-6876 of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 Kyung-Sang Yu (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for Cmax and 1.0167 (0.9347–1.1059), 0.9575 https://orcid.org/0000-0003-0921-7225 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUClast, respectively. Both the FDC and Funding loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/ This study was sponsored by Boryung hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding Pharmaceutical Co., Ltd., Seoul, Republic loose combination, and both treatments were well tolerated. of Korea. All the authors have no competing interests to declare. Keywords: Fixed-dose Combination; Fimasartan; Amlodipine; Hydrochlorothiazide; Pharmacokinetics https://tcpharm.org 53 Pharmacokinetic comparison between a fixed-dose combination and a corresponding loose combination Reviewer INTRODUCTION This article was reviewed by peer experts who are not TCP editors. Uncontrolled hypertension increases the risk of cardiovascular diseases, which may lead to Conflict of Interest sudden death [1]. Controlling blood pressure with proper treatments is important because - Authors: Nothing to declare it can decrease the risk of cardiovascular, cerebrovascular, and renal diseases caused by - Reviewers: Nothing to declare hypertension [2]. According to the 2018 ESC/ESH guidelines, a single pill with dual low-dose - Editors: Nothing to declare combination therapy is recommended as the first-line therapy for all kinds of hypertension. Author Contributions If a full-dose fixed-dose combination (FDC) is not sufficient to control hypertension, triple Conceptualization: Yu KS; Project combinations of angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), administration: Lee S1, Yu KS; Software: Lee and thiazide-like diuretics are recommended [3,4]. Patients with hypertension often need D; Supervision: Oh J; Visualization: Jung J; multiple medications and frequently have other chronic diseases requiring additional Writing - original draft: Jung J; Writing - review medications [1]. & editing: Lee S1, Oh J, Lee S2, Jang IJ, Lee D, Yu KS. Fimasartan is one of the ARBs commonly prescribed with other antihypertensive agents. 1 2 Lee S , Soyoung Lee; Lee S , SeungHwan Lee. The efficacy and safety of fimasartan for the treatment of hypertensive patients have been demonstrated in previous clinical studies [5-8]. Amlodipine, a CCB class agent, is frequently used with ARBs as combination therapy for hypertension. Additionally, hydrochlorothiazide, a thiazide-type diuretic class agent, is commonly used as an add-on drug to other antihypertensive therapies [9]. Moreover, combination therapy of thiazides with ARBs or CCBs can have a beneficial effect in terms of safety. ARBs and CCBs can cause sodium retention as a side effect, and thiazides can compensate for those effects by promoting the urinary excretion of sodium [10]. However, medical treatments with multiple medications cause patient nonadherence, resulting in treatment failure [11-13]. The FDC of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs [14-16]. In terms of cost-effectiveness, FDC has the potential to lessen health costs by reducing the pill burden, referred to as polypharmacy [17]. Currently, FDCs of dual antihypertensive agents (fimasartan with amlodipine or fimasartan with hydrochlorothiazide) are approved as initial combination therapy in Korea [18-20]. According to the Korean society of hypertension when dual combination therapy of a CCB and an ARB is inadequate for blood pressure control, the next step is applied by adding another antihypertensive agent. Diuretic is recommended to add on the initial dual combination therapy [21]. To improve patient compliance with triple-combination therapy with antihypertensive drugs, the FDC of fimasartan, amlodipine, and hydrochlorothiazide is under clinical development. Based on these understandings, this study aimed to compare the pharmacokinetic (PK) characteristics and tolerability profile of a triple-combination FDC (fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg) and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. METHODS Study population and study design A randomized, open-label, single-dose, partially replicated crossover study was performed in healthy subjects. Subjects aged 19 to 50 were recruited for the study. Subjects' health status https://tcpharm.org https://doi.org/10.12793/tcp.2021.29.e5 54 Pharmacokinetic comparison between a fixed-dose combination and a corresponding loose combination was determined by physical examination, clinical laboratory tests, 12-lead ECG, serology (HBsAg, anti-HCV, anti-HIV antibody), and urinary drug screening. Subjects who had systolic blood pressure (SBP) ≤ 100 mmHg or ≥ 140 mmHg and diastolic blood pressure (DBP) ≤ 60 mmHg or ≥ 90 mmHg were excluded from the study. Eligible subjects were hospitalized in the Seoul National University Hospital clinical trial center on the day before administration of the study drug for each period. A triple-combination FDC (fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg, Boryung Pharmaceutical Co. Ltd. Seoul, Republic of Korea) tablet was used as the test drug (T), and the loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg, Boryung Pharmaceutical Co. Ltd. Seoul, Republic of Korea), and hydrochlorothiazide 25 mg (Yuhan, Seoul, Republic of Korea) was used as the reference drug (R). The study was conducted in two-treatment, three-period, three- sequence, partially replicated crossover design. Each of three sequences consisted of a single oral administration of the test drug (T) in one period and the reference drug (R) in the other two periods (Sequence A: Reference drug, Reference drug, Test drug; Sequence B: Reference drug, Test drug, Reference drug; Sequence C: Test drug, Reference drug, Reference drug in order). The subjects were randomly assigned to one of the three sequences (Fig. 1) and received the allocated treatment in each period with a 14-day washout. For the PK analysis of fimasartan, amlodipine and hydrochlorothiazide, serial blood samples were obtained using sodium heparin tubes. Serial blood samples were collected at 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 hours of post-dose for fimasartan; at 0, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, and 144 hours of post-dose for amlodipine; and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12, 24, 36, and 48 hours of post-dose for hydrochlorothiazide. Blood samples were centrifuged at 3,000 rpm
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