PMID- 31119689 OWN - NLM STAT- MEDLINE DCOM- 20200522 LR - 20200522 IS - 1865-8652 (Electronic) IS - 0741-238X (Linking) VI - 36 IP - 7 DP - 2019 Jul TI - Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers. PG - 1642-1656 LID - 10.1007/s12325-019-00976-9 [doi] AB - 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 (C(max,ss)) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUC(tau,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. FAU - Seong, Sook Jin AU - Seong SJ AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Ohk, Boram AU - Ohk B AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Kang, Woo Youl AU - Kang WY AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Gwon, Mi-Ri AU - Gwon MR AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Kim, Bo Kyung AU - Kim BK AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Cho, Seungil AU - Cho S AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Yang, Dong Heon AU - Yang DH AD - Division of Cardiology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. FAU - Lee, Hae Won AU - Lee HW AUID- ORCID: 0000-0001-7299-5332 AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. haewonbbc@gmail.com. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. haewonbbc@gmail.com. FAU - Yoon, Young-Ran AU - Yoon YR AD - Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. yry@knu.ac.kr. AD - Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea. yry@knu.ac.kr. LA - eng SI - CRiS/KCT0001660 SI - figshare/10.6084/m9.figshare.8048198 GR - HI14C2750/Korea Health Industry Development Institute/International GR - HI15C0001/Korea Health Industry Development Institute/International GR - 10051129/Ministry of Trade, Industry and Energy/International PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190522 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 1J444QC288 (Amlodipine) RN - 80M03YXJ7I (Valsartan) RN - 83MVU38M7Q (Rosuvastatin Calcium) MH - Adult MH - *Amlodipine/administration & dosage/pharmacokinetics MH - Cross-Over Studies MH - Dose-Response Relationship, Drug MH - *Drug Interactions MH - Drug Monitoring/*methods MH - Healthy Volunteers MH - Humans MH - Hypertension/drug therapy MH - Male MH - Middle Aged MH - *Rosuvastatin Calcium/administration & dosage/pharmacokinetics MH - *Valsartan/administration & dosage/pharmacokinetics OTO - NOTNLM OT - Amlodipine OT - Drug-drug interaction OT - Rosuvastatin OT - Valsartan EDAT- 2019/05/24 06:00 MHDA- 2020/05/23 06:00 CRDT- 2019/05/24 06:00 PHST- 2019/03/25 00:00 [received] PHST- 2019/05/24 06:00 [pubmed] PHST- 2020/05/23 06:00 [medline] PHST- 2019/05/24 06:00 [entrez] AID - 10.1007/s12325-019-00976-9 [pii] AID - 10.1007/s12325-019-00976-9 [doi] PST - ppublish SO - Adv Ther. 2019 Jul;36(7):1642-1656. doi: 10.1007/s12325-019-00976-9. Epub 2019 May 22.