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Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects.
Clin Ther. 2017 Jul; 39(7):1371-1379.CT

Abstract

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 Cmax and the area under the curve from time 0 to the last measurable concentration (AUC0-last) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using Cmax and AUC0-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 Cmax and AUC0-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.

Authors+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.R&D Center, HANLIM Pharm. Co., Ltd., Seoul, Republic of Korea.Analytical/Clinical Research team, Biocore Co. Ltd., Seoul, Republic of Korea.Analytical/Clinical Research team, Biocore Co. Ltd., Seoul, Republic of Korea.College of Pharmacy, Dankook University, Cheonan, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address: sylee@skku.ac.kr.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

28625505

Citation

Oh, Mi Jin, et al. "Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects." Clinical Therapeutics, vol. 39, no. 7, 2017, pp. 1371-1379.
Oh MJ, Hwang HH, Kim HG, et al. Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. Clin Ther. 2017;39(7):1371-1379.
Oh, M. J., Hwang, H. H., Kim, H. G., Lee, G. H., Cho, Y. S., Lee, S. Y., Kang, S. Y., Cho, K. H., Lee, Y. Y., Lee, Y. J., Jang, C. G., & Lee, S. Y. (2017). Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. Clinical Therapeutics, 39(7), 1371-1379. https://doi.org/10.1016/j.clinthera.2017.05.355
Oh MJ, et al. Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. Clin Ther. 2017;39(7):1371-1379. PubMed PMID: 28625505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. AU - Oh,Mi Jin, AU - Hwang,Hyun Hwan, AU - Kim,Hyun Gyu, AU - Lee,Geun Hyeog, AU - Cho,Yun-Seok, AU - Lee,Sun Young, AU - Kang,Soo Yeon, AU - Cho,Kyung Hee, AU - Lee,Yun Young, AU - Lee,Yun Jeong, AU - Jang,Choon-Gon, AU - Lee,Seok-Yong, PY - 2016/11/18/received PY - 2017/02/19/revised PY - 2017/05/24/accepted PY - 2017/6/20/pubmed PY - 2017/12/27/medline PY - 2017/6/20/entrez KW - S-amlodipine KW - bioequivalence KW - olmesartan KW - pharmacokinetics SP - 1371 EP - 1379 JF - Clinical therapeutics JO - Clin Ther VL - 39 IS - 7 N2 - 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 Cmax and the area under the curve from time 0 to the last measurable concentration (AUC0-last) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using Cmax and AUC0-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 Cmax and AUC0-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. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/28625505/Bioequivalence_Study_of_a_New_Fixed_dose_Combination_Tablet_Containing_S_Amlodipine_Nicotinate_and_Olmesartan_Medoxomil_in_Healthy_Korean_Male_Subjects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(17)30664-1 DB - PRIME DP - Unbound Medicine ER -