Moon Seol Ju, Jeon Ji-Young, Jang Kyungho, Yu Kyung-Sang, Lim Yeji, Kim Min-Gul
Center for Clinical Pharmacology, Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Drug Des Devel Ther. 2019 Jul 25;13:2533-2542. doi: 10.2147/DDDT.S210364. eCollection 2019.
Hypertension and dyslipidemia are major risk factors for cardiovascular diseases, and reduction of cardiovascular risks can be achieved by combining antihypertensive therapy with statins. The objective of this study was to evaluate the pharmacokinetic interaction between telmisartan/amlodipine fixed dose combination and rosuvastatin in healthy Korean male volunteers.
An open-label, two-cohort, multiple-dose, single-sequence crossover study was conducted in healthy male subjects. In Cohort 1, the subjects were administered one tablet of telmisartan/amlodipine 80 mg/5 mg once daily for 14 days with or without one tablet of rosuvastatin 20 mg once daily. In Cohort 2, the subjects were administered one tablet of rosuvastatin 20 mg once daily for 14 days with or without one tablet of telmisartan/amlodipine 80 mg/5 mg once daily. Serial blood samples were collected up to 24 hrs post-dose on the 9th and 14th days in Cohort 1 and on the 5th and 14th days in Cohort 2. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration at steady state (C) and area under the plasma concentration versus time curve over dosing interval (AUC), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of log-transformed C and AUC for separate or concurrent therapy were calculated to evaluate pharmacokinetic interactions.
Thirty-eight subjects from Cohort 1 and nineteen subjects from Cohort 2 completed the study. The GLSM ratios and 90% CIs of C and AUC were 0.9829 (0.8334-1.1590) and 1.0003 (0.9342-1.0710) for telmisartan; 0.9908 (0.9602-1.0223) and 1.0081 (0.9758-1.0413) for amlodipine; and 2.2762 (2.0113-2.5758) and 1.3261 (1.2385-1.4198) for rosuvastatin, respectively.
The pharmacokinetic parameters of telmisartan/amlodipine, but not rosuvastatin, met the pharmacokinetic equivalent criteria. The increase in systemic exposure to rosuvastatin caused by telmisartan/amlodipine co-administration would not be clinically significant in practice. Nevertheless, an appropriately designed two-sequence crossover study is needed to confirm the results of this study.
高血压和血脂异常是心血管疾病的主要危险因素，联合使用抗高血压药物和他汀类药物可降低心血管疾病风险。本研究的目的是评估替米沙坦/氨氯地平固定剂量复方制剂与瑞舒伐他汀在健康韩国男性志愿者中的药代动力学相互作用。
在健康男性受试者中进行了一项开放标签、双队列、多剂量、单序列交叉研究。在队列1中，受试者每天服用1片替米沙坦/氨氯地平80毫克/5毫克，持续14天，同时或不同时每天服用1片瑞舒伐他汀20毫克。在队列2中，受试者每天服用1片瑞舒伐他汀20毫克，持续14天，同时或不同时每天服用1片替米沙坦/氨氯地平80毫克/5毫克。在队列1的第9天和第14天以及队列2的第5天和第14天，给药后24小时内连续采集血样。采用液相色谱/串联质谱法测定血浆药物浓度。通过非房室分析确定药代动力学参数，包括稳态时的最大血浆浓度（C）和给药间隔内血浆浓度-时间曲线下面积（AUC）。计算单独或联合治疗时log转换后的C和AUC的几何最小二乘均值（GLSM）比值及相关的90%置信区间（CI），以评估药代动力学相互作用。
队列1的38名受试者和队列2的19名受试者完成了研究。替米沙坦的C和AUC的GLSM比值及90%CI分别为0.9829（0.8334-1.1590）和1.0003（0.9342-1.0710）；氨氯地平的分别为0.9908（0.9602-1.0223）和1.0081（0.9758-1.0413）；瑞舒伐他汀的分别为2.2762（2.0113-2.5758）和1.3261（1.2385-1.4198）。
替米沙坦/氨氯地平的药代动力学参数符合药代动力学等效标准，而瑞舒伐他汀不符合。替米沙坦/氨氯地平联合给药导致瑞舒伐他汀全身暴露量增加在实际临床中无显著意义。然而，需要进行适当设计的双序列交叉研究来证实本研究结果。
