Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers

Abstract

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

“…14 Plasma aliskiren levels were measured by a high-performance liquid chromatography/mass spectrometry-mass spectrometry method with a lower limit of quantification of 0.5 ng/mL (Novartis Laboratories). 15 Renin concentration was measured with a commercial immunoradiometric kit (Renin III, Cisbio, Gifsur-Yvette, France). 16 Total renin concentration was determined simultaneously with the same kit after the induction of a conformational change in the prorenin molecule with aliskiren (10 mol/L for 48 hours at 4°C), which enabled its recognition by the active site-directed radiolabeled antibodies applied in the Cisbio kit.…”

Renin Inhibition in Hypertension

“…After a single intravenous infusion of 20 mg in healthy males, the plasma clearance of aliskiren was approximately 9 l/h, and the hepatic extraction ratio was approximately 10% with only minor involvement of the first-pass metabolism (46). The volume of distribution was approximately 135 l. In humans, aliskiren is 47% to 51% protein bound (47).…”

Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases

“…[9,25] Aliskiren concentrations are greater in the kidney than in plasma and the drug is detectable in the kidney up to three weeks after discontinuation of therapy, whereas plasma levels of aliskiren are undetectable at this time point. [18,28] After oral administration, peak plasma concentrations of aliskiren are reached within 1-3 h [14,29] and steady-state blood levels are reached in about 7-8 days with once-daily administration. [25] The plasma half-life of aliskiren in rats, marmosets and humans shows a slow terminal elimination at 23, 26 and 23-40 h, respectively.…”

“…Aliskiren 300 mg Aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects 38 Vaidyanathan et al [29] 2006…”