Lee Donghwan, Roh Hyerang, Son Hankil, Jang Seong Bok, Lee Seoungoh, Nam Su Youn, Park Kyungsoo
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
Yuhan Research Institute, Yuhan Corporation, Seoul, Korea.
Clin Ther. 2014 Aug 1;36(8):1171-81. doi: 10.1016/j.clinthera.2014.06.004. Epub 2014 Jun 26.
Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.
This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.
Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin Css,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUCtau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for Css,max and AUCtau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.
Although the Css,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.
瑞舒伐他汀用于治疗高胆固醇血症或血脂异常，二甲双胍主要用于治疗2型糖尿病。由于这两种疾病的高共病率，这两种药物经常联合使用。然而，这两种药物之间的药代动力学相互作用的性质此前尚未得到研究。我们研究的目的是在健康的韩国男性志愿者中研究瑞舒伐他汀和二甲双胍之间的药代动力学相互作用。
这是一项随机、开放标签、6序列、3周期、交叉、多剂量研究。符合条件的受试者年龄在20至50岁之间，体重在理想体重的20%以内，每个周期接受以下3种治疗中的1种，每天1次，连续5天，治疗之间有10天的洗脱期：单剂量服用10毫克瑞舒伐他汀片、单剂量服用750毫克二甲双胍片、联合服用10毫克瑞舒伐他汀片和750毫克二甲双胍片。在最后一剂后最多72小时采集血样，比较联合治疗和单药治疗时瑞舒伐他汀和二甲双胍的药代动力学参数。通过受试者访谈和体格检查来调查和评估不良事件。
在36名入选受试者中，31名完成了研究。瑞舒伐他汀与二甲双胍联合给药在瑞舒伐他汀的稳态血药浓度峰值（Css,max）上产生了显著的药代动力学相互作用，几何平均比值（联合给药：单药给药）的90%置信区间为110.27%至136.39%（P = 0.0029），而在瑞舒伐他汀的药时曲线下面积（AUCtau）方面未观察到显著相互作用，其90%置信区间为104.41%至118.95%。当二甲双胍与瑞舒伐他汀联合给药时，二甲双胍的Css,max和AUCtau未观察到显著的药代动力学相互作用，联合给药与单药给药的几何平均比值的90%置信区间分别为87.38%至102.54%和86.70%至99.08%。总体而言，12名受试者发生了19例轻度和1例中度不良事件，3种治疗之间的发生率无显著差异。
虽然瑞舒伐他汀的Css,max受到与二甲双胍联合给药的显著影响，但观察到的相互作用程度在临床上被认为无显著意义，这两种药物在其他药代动力学指标上未观察到显著相互作用。这些结果表明，瑞舒伐他汀和二甲双胍的药物效应也不会受到这两种药物联合给药的显著影响。所有治疗耐受性良好，未发生严重不良事件。ClinicalTrials.gov标识符：NCT01526317。
