Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Waldmeier, Felix; Glaenzel, Ulrike; Wirz, Beat; Oberer, Lukas; Schmid, Dietmar G.; Seiberling, Michael; Valencia, Jessica; Riviere, Gilles-Jacques; End, Peter; Vaidyanathan, Sujata

doi:10.1124/dmd.106.013797

Cited by 121 publications

(103 citation statements)

References 29 publications

(27 reference statements)

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“…Aliskiren has a molecular weight (551.8) small enough to be filtered by the glomerulus, and indeed the drug appears in the urine. 83 Thus, in vivo exposure of podocytes to aliskiren is predicted. As podocytes express a functional RAAS, [25][26][27][28] renin inhibition in these cells by aliskiren may Effect of aliskiren and enalapril on blood pressure (a) and albumin excretion (b) in mRen-2 rats.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…5 Aliskiren exhibits a long terminal elimination half-life of approximately 40 h, 6,7 and has shown effective 24-h BP control in ambulatory BP-monitoring substudies. 8 Moreover, clinical studies in patients with hypertension have shown that the effect of aliskiren to lower BP and reduce plasma renin activity (PRA) persists for up to 2 weeks after stopping treatment.…”

Section: Introductionmentioning

confidence: 99%

Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

et al. 2009

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Most patients inadvertently miss an occasional dose of antihypertensive therapy, and hence drugs that provide sustained blood-pressure (BP) reduction beyond the 24-h dosing interval are desirable. The primary objective of this study was to compare the 24-h mean ambulatory BP reductions from baseline after a simulated missed dose of the direct renin inhibitor aliskiren, irbesartan or ramipril. In this double-blind study, 654 hypertensive patients (24-h mean ambulatory diastolic BP (MADBP) X85 mm Hg) were randomized 1:1:1 to once-daily aliskiren 150 mg, irbesartan 150 mg or ramipril 5 mg. Doses were doubled after 2 weeks. At day 42, patients were again randomized equally within each group to receive 1 day of placebo ('missed dose') on either day 42 or day 49. Patients with a successful 24-h ambulatory BP measurement at baseline and on day 42/49 were included in the analyses. The 24-h mean ambulatory systolic BP (MASBP)/MADBP reductions from baseline after a missed dose of aliskiren 300 mg (9.3/7.0 mm Hg) were similar to irbesartan 300 mg (9.5/7.3 mm Hg) and significantly larger than ramipril 10 mg (7.1/5.0 mm Hg, Pp0.008). Loss of BP-lowering effect with aliskiren in the 24 h after a missed dose (1.0/0.7 mm Hg for 24-48-h vs 0-24-h MASBP/MADBP) was significantly lower than with irbesartan (3.6/2.2 mm Hg, Po0.01) or ramipril (4.0/2.6, Po0.0001). This equates to maintenance of 91/91% of the MASBP/MADBP-lowering effect with aliskiren, greater than irbesartan (73/77%) or ramipril (64/65%). The incidence of adverse events was similar across treatments (32.9-36.0%), although ramipril treatment was associated with an increased incidence of cough (ramipril, 6.1%; aliskiren, 0.5%; irbesartan, 1.8%). Aliskiren 300 mg provided a sustained BP-lowering effect beyond the 24-h dosing interval, with a significantly smaller loss of BP-lowering effect in the 24-48 h period after dose than irbesartan 300 mg or ramipril 10 mg.

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“…Aliskiren is primarily eliminated by the hepatobiliary route as unmetabolized drug. Less than 1% of an orally administered dose is excreted in the urine as unchanged drug (Waldmeier et al, 2007). After oral administration of a single 300-mg dose of aliskiren to healthy volunteers, the mean ± SD clearance corrected for bioavailability [i.e., clearance/drug bioavailability (Cl/F)] was 234 ± 137 L/hour (Zhao et al, 2006).…”

Section: Pharmacokinetic Properties Of Aliskirenmentioning

confidence: 99%

“…The pharmacokinetic properties of aliskiren have been studied in animals, healthy human subjects, patients with compromised liver and kidney function, and subjects with mild hypertension (Waldmeier et al, 2007). Aliskiren has a poor bioavailability (2-6%), but this is compensated by its high solubility and the already mentioned high inhibitory effect (IC 50 = 0.6 nM) from in vitro inhibition of human renin (Wood et al, 2005;Azizi et al, 2006).…”

Section: Pharmacokinetic Properties Of Aliskirenmentioning

confidence: 99%

Efficacy of Aliskiren/Hydrochlorothiazide Combination for the Treatment of Hypertension: A Meta-Analytical Revision

Morgado¹,

Rolo²,

Castelo‐Branco³

2012

Pharmacotherapy

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Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Abstract: Aliskiren (2(S),4(S),5(S),7(S)-

Cited by 121 publications

References 29 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

Efficacy of Aliskiren/Hydrochlorothiazide Combination for the Treatment of Hypertension: A Meta-Analytical Revision

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