Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine.
OBJECTIVE
Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities.


METHODS
Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18-45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data.


RESULTS
Mean AUC and t1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean Cmax was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, Cmax and t1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib.


CONCLUSIONS
Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.
Dieterle
W
W
Drug Disposition Consultants, Lörrach, Germany.
Corynen
S
S
Vaidyanathan
S
S
Mann
J
J
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D000577:Amides; D001262:Atenolol / Q000097:blood / Q000493:pharmacokinetics*; D000068579:Celecoxib; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D005650:Fumarates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D006973:Hypertension / Q000188:drug therapy; D008148:Lovastatin / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D000092502:Renin Inhibitors
D000319:Adrenergic beta-Antagonists; D000577:Amides; D001262:Atenolol; D000068579:Celecoxib; D002927:Cimetidine; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D005650:Fumarates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D011720:Pyrazoles; D013449:Sulfonamides; D000092502:Renin Inhibitors; C446481:aliskiren