A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects

作者：Vaidyanathan Sujata; Maboudian Mojdeh; Warren Vance; Yeh Ching Ming; Dieterich Hans Armin; Howard Dan; Dole William P^*

来源：Current Medical Research and Opinion, 2008, 24(8): 2313-2326.

DOI：10.1185/03007990802259354

• antihypertensives
• type 2 diabetes mellitus
• drug interaction
• pharmacokinetics
• lipid-lowering

Objective: 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 feno-fibrate in healthy volunteers.
Methods: 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.
Results: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration-time curve during the dose interval (AUC(r)) 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. Go-administration of aliskiren with fenofibrate had no effect on aliskiren AUG, (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 AUG, (GMR 1.05; 90% CI 0.98, 1.13) or C-max (GMR 1.01; 90% CI 0.84, 1.20). All other AUG, and Cm. GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglitazone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25.
Conclusion: 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.

• 出版日期2008-8