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

ABSTRACT

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 fenofibrate 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_τ) 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_τ (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_τ (GMR 1.05; 90% CI 0.98, 1.13) or C_max (GMR 1.01; 90% CI 0.84, 1.20). All other AUC_τ and C_max 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.

Key words: :

• Antihypertensives
• Type 2 Diabetes mellitus
• Drug interaction
• Pharmacokinetics
• Lipid-lowering

Acknowledgements

Declaration of interest: This work was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. All authors are employees of Novartis Pharmaceuticals Corporation, and are thus eligible for Novartis stock and stock options.

The authors thank Drs Ann Taylor and Jenny Handford (Oxford PharmaGenesis Ltd) for assistance in collating and incorporating comments from all authors to produce a final draft manuscript for submission. This medical writing assistance was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

The authors take full responsibility for the contents of the article, and all authors participated in the development and writing of the paper, and approved the final manuscript.

Notes

* Results presented at the 108th American Society for Clinical Pharmacology and Therapeutics meeting, USA; 21–24 Mar 2007; and the 8th Congress of the European Association for Clinical Pharmacology and Therapeutics, the Netherlands; 29 Aug–1 Sep 2007