Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers
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Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug–drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers.
In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography–tandem mass spectrometry.
Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration–time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029–0.9763) and 0.9316 (0.8970–0.9675) for amlodipine, 0.7698 (0.6503–0.9114) and 0.7888 (0.6943–0.8962) for valsartan, and 0.9737 (0.8312–1.1407) and 0.9596 (0.8826–1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported.
When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated.
Clinical Trial Registration
https://cris.nih.go.kr CRIS KCT0001660.
KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
KeywordsAmlodipine Drug–drug interaction Rosuvastatin Valsartan
The authors thank all participants of the study.
This study and article processing charges were sponsored by KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea, and was supported by Grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C2750, HI15C0001), and the Industrial Core Technology Development Program (10051129, Development of the system for ADME assessment using radiolabeled compounds), funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea). All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Medical Writing and/or Editorial Assistance
Medical writing support was provided by Vikas Narang of Editage by Cactus Communications Inc. (Trevose, PA, USA), and was funded by KNUH CTC.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Sook Jin Seong, Boram Ohk, Woo Youl Kang, Mi-Ri Gwon, Bo Kyung Kim, Seungil Cho, Dong Heon Yang, Hae Won Lee, and Young-Ran Yoon have nothing to disclose.
Compliance with Ethics Guidelines
The study protocol was approved by the Institutional Review Board at Kyungpook National University Hospital (Daegu, Republic of Korea), and the study was performed in accordance with the ethical standards for studies in humans set out in the Declaration of Helsinki and its amendments, and the applicable guidelines for International Conference on Harmonization Good Clinical Practice, and local laws and regulations. Written informed consent was obtained from all individual subjects included in the study before their enrollment.
The data sets generated and/or analyzed during this study are not publicly available due to confidentiality of KyungDong Pharmaceutical Corp. Ltd., but are available from the corresponding author upon reasonable request.
- 1.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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;106:3143–421.Google Scholar
- 7.Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219.CrossRefPubMedGoogle Scholar
- 9.Pfizer Pharmaceuticals Co. NOVASC drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019787s053lbl.pdf. Accessed 20 Aug 2018.
- 16.Novartis Pharmaceuticals Co. Diovan drug label. pdf. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021283s035lbl. Accessed 22 Aug 2018.
- 21.Crestor (rosuvastatin calcium) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021366s030lbl.pdf. Accessed 24 Aug 2018.