Vaidyanathan Sujata, Maboudian Mojdeh, Warren Vance, Yeh Ching-Ming, Dieterich Hans Armin, Howard Dan, Dole William P
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Curr Med Res Opin. 2008 Aug;24(8):2313-26. doi: 10.1185/03007990802259354.
Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers.
In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations.
Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration- time curve during the dose interval (AUC(tau)) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C(max)) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC (GMR 1.05; 90% CI 0.96, 1.16) or C(max) (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC(tau) (GMR 1.05; 90% CI 0.98, 1.13) or C(max) (GMR 1.01; 90% CI 0.84, 1.20). All other AUC and C(max) GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglita-zone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25.
Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.
高血压和2型糖尿病是常见的合并症，因此许多接受抗高血压药物治疗的患者需要同时使用降糖或降脂药物。这三项研究的目的是调查在健康志愿者中，直接肾素抑制剂阿利吉仑与降糖药物二甲双胍或吡格列酮或降脂药物非诺贝特联合使用治疗高血压时的药代动力学、安全性和耐受性。
在三项开放标签、多剂量研究中，健康志愿者（年龄18至45岁）接受每日一次的治疗，分别为二甲双胍1000毫克（n = 22）、吡格列酮45毫克（n = 30）或非诺贝特200毫克（n = 21）以及阿利吉仑300毫克，单独给药或在两阶段研究设计中联合给药。在每个治疗期的最后一天频繁采集血样以测定血浆药物浓度。
阿利吉仑与二甲双胍联合使用使剂量间隔期间阿利吉仑的血浆浓度 - 时间曲线下面积（AUC(tau)）降低了27%（几何平均比值[GMR] 0.73；90%置信区间[CI] 0.64，0.84），最大观察血浆浓度（C(max)）降低了29%（GMR 0.71；90% CI 0.56，0.89），但这些变化不被认为具有临床相关性。阿利吉仑与非诺贝特联合使用对阿利吉仑的AUC（GMR 1.05；90% CI 0.96，1.16）或C(max)（GMR 1.05；90% CI 0.80，1.38）没有影响；同样，阿利吉仑与吡格列酮联合使用对阿利吉仑的AUC(tau)（GMR 1.05；90% CI 0.98，1.13）或C(max)（GMR 1.01；90% CI 0.84，1.20）没有影响。阿利吉仑、二甲双胍、吡格列酮、酮吡格列酮、羟基吡格列酮和非诺贝特的所有其他AUC和C(max) GMR均接近1，且90%置信区间包含在生物等效性范围0.80至1.25内。
阿利吉仑与二甲双胍、吡格列酮或非诺贝特联合使用对这些药物在健康志愿者中的药代动力学没有显著影响。这些发现表明阿利吉仑可以与二甲双胍、吡格列酮或非诺贝特联合使用而无需调整剂量。
