Sook Jin Seong1,2, Boram Ohk1,2, Woo Youl Kang1,2, Mi-Ri Gwon1,2, Bo Kyung Kim1,2, Seungil Cho1,2, Dong Heon Yang3, Hae Won Lee4,5, Young-Ran Yoon6,7. 1. Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 2. Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. 3. Division of Cardiology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. 4. Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. haewonbbc@gmail.com. 5. Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. haewonbbc@gmail.com. 6. Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. yry@knu.ac.kr. 7. Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. yry@knu.ac.kr.
Abstract
INTRODUCTION: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. METHODS: 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. RESULTS: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 13adverse events (AEs); no severe or serious AEs were reported. CONCLUSION: 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. FUNDING: KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
RCT Entities:
INTRODUCTION: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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. FUNDING: KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
Authors: Eline H Groenland; Monique E A M van Kleef; Michiel L Bots; Frank L J Visseren; Kim C M van der Elst; Wilko Spiering Journal: Hypertension Date: 2020-11-30 Impact factor: 10.190