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). Research design and 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% Cl, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% Cl, 1.08, 1.16]) and C (mean ratio 1.08 [90% Cl, 1.04,1.13]), with 90% Cl within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C.. (mean ratio 0.88 [90% Cl, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C-max of celecoxib (mean ratios and 90% Cl 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% Cl including 1.00, but with some 90% Cl outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC, by 20% (mean ratio 1.20 [90% Cl, 1.07, 1.34]) and C-max by 25% (mean ratio 1.25 [90% Cl, 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.