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


CONCLUSIONS
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.
Vaidyanathan
Sujata
S
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Maboudian
Mojdeh
M
Warren
Vance
V
Yeh
Ching-Ming
CM
Dieterich
Hans Armin
HA
Howard
Dan
D
Dole
William P
WP
D000293:Adolescent; D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004347:Drug Interactions; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005650:Fumarates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D000077205:Pioglitazone; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D011345:Fenofibrate; D005650:Fumarates; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008687:Metformin; D000077205:Pioglitazone; D045162:Thiazolidinediones; D000092502:Renin Inhibitors; C446481:aliskiren