PMID- 28625505 OWN - NLM STAT- MEDLINE DCOM- 20171226 LR - 20221207 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 39 IP - 7 DP - 2017 Jul TI - Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. PG - 1371-1379 LID - S0149-2918(17)30664-1 [pii] LID - 10.1016/j.clinthera.2017.05.355 [doi] AB - PURPOSE: A fixed-dose combination (FDC) pill of amlodipine (relatively old calcium channel blocker as dihydropyridine) and olmesartan (relatively new angiotensin II receptor blocker) is used for hypertension that is not adequately controlled with a single-formulation drug. Because the FDC is a one-pill formulation, and amlodipine and olmesartan have different mechanisms of action, it is expected to improve patients' medication compliance and have an increased blood pressure-lowering efficacy. The purpose of this study was to assess the safety profile and the bioequivalence of two different FDC formulations [amlodipine besylate/olmesartan medoxomil 10/40 mg (reference product) and S-amlodipine nicotinate/olmesartan medoxomil 5/40 mg (test product)]. METHODS: A randomized, open-label, single-dose, 2-treatment, 2-way, and 2-period crossover study, including a 3-week washout period, was performed in 32 healthy Korean male volunteers. To analyze the concentration of S-amlodipine or olmesartan, plasma samples were collected up to 144 hours after the dose for S-amlodipine and 48 hours after the dose for olmesartan. Pharmacokinetic parameters, including the C(max) and the area under the curve from time 0 to the last measurable concentration (AUC(0-last)) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using C(max) and AUC(0-last) converted to log scale, and the mean ratios and 90% CIs were determined. Safety data included analysis of adverse events (AEs), vital signs, physical examinations, clinical laboratory test, and 12-lead ECGs. FINDINGS: Of the 32 enrolled participants, 29 healthy volunteers completed the study. For both S-amlodipine and olmesartan, the main pharmacokinetic parameters were all within the acceptable range for regulatory bioequivalence. The 90% CIs for the geometric mean ratios of C(max) and AUC(0-last) were 0.8766 to 0.9760 and 0.8288 to 0.9224, respectively, for S-amlodipine and 0.9097 to 1.1229 and 0.8904 to 1.0407, respectively, for olmesartan. Hypotension was the most frequent AE, and it was observed in 4 volunteers with the test product and 7 volunteers with the reference product. Both the test and reference formulations were well tolerated. IMPLICATIONS: The present study demonstrates that the newly developed FDC product (test drug) and the conventional FDC product (reference drug) have comparable pharmacokinetic characteristics in healthy adult male volunteers. Both the test and reference products indicated good tolerance in this population, and no serious AEs were observed. CI - Copyright (c) 2017 Elsevier HS Journals, Inc. All rights reserved. FAU - Oh, Mi Jin AU - Oh MJ AD - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Hwang, Hyun Hwan AU - Hwang HH AD - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. FAU - Kim, Hyun Gyu AU - Kim HG AD - R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Lee, Geun Hyeog AU - Lee GH AD - R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Cho, Yun-Seok AU - Cho YS AD - R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Lee, Sun Young AU - Lee SY AD - R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Kang, Soo Yeon AU - Kang SY AD - R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea. FAU - Cho, Kyung Hee AU - Cho KH AD - Analytical/Clinical Research team, Biocore Co. Ltd., Seoul, Republic of Korea. FAU - Lee, Yun Young AU - Lee YY AD - Analytical/Clinical Research team, Biocore Co. Ltd., Seoul, Republic of Korea. FAU - Lee, Yun Jeong AU - Lee YJ AD - College of Pharmacy, Dankook University, Cheonan, Republic of Korea. FAU - Jang, Choon-Gon AU - Jang CG AD - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. FAU - Lee, Seok-Yong AU - Lee SY AD - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address: sylee@skku.ac.kr. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Angiotensin II Type 1 Receptor Blockers) RN - 0 (Calcium Channel Blockers) RN - 0 (Drug Combinations) RN - 0 (Tablets) RN - 0 (amlodipine nicotinate) RN - 1J444QC288 (Amlodipine) RN - 2679MF687A (Niacin) RN - 6M97XTV3HD (Olmesartan Medoxomil) SB - IM MH - Adult MH - Amlodipine/administration & dosage/blood/*pharmacokinetics MH - Angiotensin II Type 1 Receptor Blockers/administration & dosage/blood/*pharmacokinetics MH - Asian People MH - Calcium Channel Blockers/administration & dosage/blood/*pharmacokinetics MH - Cross-Over Studies MH - Drug Combinations MH - Healthy Volunteers MH - Humans MH - Male MH - Niacin/administration & dosage/blood/*pharmacokinetics MH - Olmesartan Medoxomil/administration & dosage/blood/*pharmacokinetics MH - Tablets MH - Therapeutic Equivalency MH - Young Adult OTO - NOTNLM OT - S-amlodipine OT - bioequivalence OT - olmesartan OT - pharmacokinetics EDAT- 2017/06/20 06:00 MHDA- 2017/12/27 06:00 CRDT- 2017/06/20 06:00 PHST- 2016/11/18 00:00 [received] PHST- 2017/02/19 00:00 [revised] PHST- 2017/05/24 00:00 [accepted] PHST- 2017/06/20 06:00 [pubmed] PHST- 2017/12/27 06:00 [medline] PHST- 2017/06/20 06:00 [entrez] AID - S0149-2918(17)30664-1 [pii] AID - 10.1016/j.clinthera.2017.05.355 [doi] PST - ppublish SO - Clin Ther. 2017 Jul;39(7):1371-1379. doi: 10.1016/j.clinthera.2017.05.355.