A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with allopurinol, celecoxib and cimetidine in healthy subjects.
OBJECTIVE
Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters).


METHODS
Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS.


RESULTS
Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]).


CONCLUSIONS
In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.
Ayalasomayajula
Surya
S
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. surya.ayalasomayajula@novartis.com
Tchaloyan
Stéphanie
S
Yeh
Ching-Ming
CM
Bizot
Marie-Noelle
MN
Dieterich
Hans Armin
HA
Howard
Dan
D
Dole
William P
WP
D000293:Adolescent; D000328:Adult; D000493:Allopurinol / Q000097:blood / Q000493:pharmacokinetics*; D000577:Amides / Q000097:blood / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics; D000068579:Celecoxib; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics*; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005650:Fumarates / Q000097:blood / Q000493:pharmacokinetics*; D006074:Gout Suppressants / Q000493:pharmacokinetics; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D000092502:Renin Inhibitors
D000493:Allopurinol; D000577:Amides; D000959:Antihypertensive Agents; D000068579:Celecoxib; D002927:Cimetidine; D016861:Cyclooxygenase Inhibitors; D005650:Fumarates; D006074:Gout Suppressants; D006635:Histamine H2 Antagonists; D011720:Pyrazoles; D013449:Sulfonamides; D000092502:Renin Inhibitors; C446481:aliskiren