Drug Design, Development and Therapy (Feb 2020)
Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers
Abstract
Deok Yong Yoon,1 Sang-In Park,2 Jin-A Jung,3 Yong-Il Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of KoreaCorrespondence: Jae-Yong ChungDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of KoreaTel +82-31-787-3955Fax +82-31-787-4045Email [email protected]: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.Subjects and Methods: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study.Results: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663– 1.0238) and 0.9690 (0.9379– 1.0011) for amlodipine, 0.9855 (0.9422– 1.0308) and 0.9178 (0.8349– 1.0089) for losartan, 0.9814 (0.9501– 1.0136) and 0.9756 (0.9313– 1.0219) for EXP3174, and 0.9448 (0.8995– 0.9923) and 0.9609 (0.8799– 1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.Conclusion: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.Keywords: fixed-dose combination, loose combination, bioequivalence, pharmacokinetics, hypertension, dyslipidemia
