Pharmacokinetics of the Oral Direct??Renin Inhibitor Aliskiren Alone and??in Combination with Irbesartan in??Renal Impairment

Vaidyanathan, Sujata; Bigler, Hilde; Yeh, Ching Ming; Bizot, Marie-Noelle; Dieterich, H. A.; Howard, David L.; Dole, William P.

doi:10.2165/00003088-200746080-00003

Cited by 67 publications

(43 citation statements)

References 24 publications

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“…In this study, aliskiren may have decreased biomarkers for CVD by improving intracellular signaling and vascular endothelial function by decreasing inflammatory mediators but not by increasing natriuresis in addition to a BP-lowering effect because all enrolled patients had oliguria or anuria. Further studies will need to investigate the mechanism of cardiovascular protective effects by aliskiren in HDD-CKD patients with hypertension Several studies reported that mean trough plasma aliskiren concentrations increased by renal impairment; 25,26 however, an increase in exposure does not correlate with the severity of renal impairment. 25 Moreover, renal clearance of aliskiren represents only a small fraction (0.1-1.0%).…”

Section: Discussionmentioning

confidence: 99%

“…Further studies will need to investigate the mechanism of cardiovascular protective effects by aliskiren in HDD-CKD patients with hypertension Several studies reported that mean trough plasma aliskiren concentrations increased by renal impairment; 25,26 however, an increase in exposure does not correlate with the severity of renal impairment. 25 Moreover, renal clearance of aliskiren represents only a small fraction (0.1-1.0%). 9 These data suggest that adjustment of the aliskiren dose is unlikely to be required in HD patients.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension

et al. 2010

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The renin-angiotensin-aldosterone system (RAAS) has pivotal roles in the pathogenesis of hypertension in hemodialysisdependent chronic kidney disease (HDD-CKD) patients. Activated RAAS also increases inflammatory mediators by directly increasing proinflammatory gene expression and by putting oxidative stress on the vascular endothelium. Both hypertension and inflammation are major risk factors for cardiovascular disease (CVD) in HDD-CKD patients. In this study, we assessed the efficacy of a direct renin inhibitor, aliskiren, on blood pressure (BP) and CVD predictive biomarkers, such as brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP) and diacron-reactive oxygen metabolite (d-ROM). A total of 30 hypertensive HDD-CKD patients were assigned to receive aliskiren (150 mg) orally once daily with their existing antihypertensives. After 8 weeks, aliskiren treatments reduced systolic blood pressure (SBP) from 169.0 ± 20.1 to 153.7 ± 19.6 mm Hg (Po0.001) and diastolic blood pressure (DBP) from 78.1 ± 12.0 to 73.0 ± 13.6 mm Hg (P¼0.048). RAAS was suppressed by aliskiren treatment as follows: PRA (from 3.6±4.0 to 1.0±1.5 ng ml -1 h -1 (P¼0.004)), angiotensin I (from 1704.0 ± 2580.9 to 233.7 ± 181.0 pg ml -1 (P¼0.009)), angiotensin II (from 70.2 ± 121.5 to 12.4 ± 11.5 pg ml -1 (P¼0.022)) and aldosterone (from 107.9 ± 148.0 to 73.1 ± 34.6 pg ml -1 (NS)). The biomarkers for CVD were inhibited by aliskiren: BNP (from 362.5±262.1 to 300.0±232.0 pg ml -1 (P¼0.043)), hS-CRP (from 6.2±8.1 to 3.5±3.7 mg l -1 (P¼0.022)) and d-ROM (from 367.0 ± 89.8 to 328.3 ± 70.9 U.CARR (P¼0.022)). The inhibition levels of biomarkers for CVD by aliskiren did not correlate with the decreased levels of SBP and DBP. These results suggested that aliskiren was effective for BP control and may have cardiovascular protective effects in hypertensive HDD-CKD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension

et al. 2010

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“…Changes in exposure did not correlate with the severity of renal insufficiency, as assessed by CL CR [19]. The accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC 24 ] on day 7 vs day 1) was similar in healthy subjects (1.79) and each subgroup of subjects with renal impairment (1.39-1.99).…”

Section: Pharmacology Of Aliskirenmentioning

confidence: 87%

“…The accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC 24 ] on day 7 vs day 1) was similar in healthy subjects (1.79) and each subgroup of subjects with renal impairment (1.39-1.99). The authors conclude that exposure to aliskiren is increased by renal impairment, but does not correlate with the severity of renal insufficiency (CL CR ); therefore, adjustment of the starting dose of aliskiren is not required in patients with renal impairment [19]. However, caution is advised in patients with severe renal impairment, especially those with sodium depletion [16].…”

Section: Pharmacology Of Aliskirenmentioning

confidence: 99%

Aliskiren – an antihypertensive renin inhibitor in the treatment of patients with chronic kidney disease

Łukawski¹,

Baranowicz-Gąszczyk²

2017

J Pre Clin Clin Res.

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Łukawski K, Baranowicz-Gąszczyk I. Aliskiren -an antihypertensive renin inhibitor in the treatment of patients with chronic kidney disease. J Pre-Clin Clin Res. 2017; 11(1): 81-85. doi: 10.26444/jpccr/75295 Abstract Introduction. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of hypertension, cardiovascular diseases (CVDs) and chronic kidney disease (CKD). Drugs affecting the RAAS system, such as angiotensinconverting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are commonly used in the treatment of hypertension and heart failure. These drugs are also effective in reducing proteinuria and may, at least, delay end-stage renal disease in both diabetic and non-diabetic proteinuric CKD. However, novel drugs are needed to more effectively suppress the RAAS system and the progression of CKD. Aliskiren is the first direct renin inhibitor which has been approved for the treatment of hypertension. Additionally, a number of clinical studies have shown the antiproteinuric effect of aliskiren.Objective. This review focuses on the antihypertensive and antiproteinuric effects of aliskiren in patients with CKD. The pharmacology of aliskiren in these patients is also provided. Conclusions. Aliskiren-based hard endpoint large trials in non-diabetic nephropathy are needed in order to clarify the use of aliskiren in CKD patients.

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“…The results from an earlier study assessing the effects of renal impairment on pharmacokinetics of aliskiren (300 mg once daily) in patients with mild-to-moderate renal dysfunction and healthy volunteers showed that although exposure is increased by renal impairment, the increase in exposure does not correlate with the severity of renal impairment. 17 Moreover, healthy volunteer studies have shown that renal excretion has a minor role in aliskiren elimination, with only 0.1-1.0% of an oral dose being excreted in urine. 8 As renal clearance of aliskiren represents a small fraction of total clearance, adjustment of the initial dose is unlikely to be required in patients with moderate renal impairment.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of aliskiren in Japanese hypertensive patients with renal dysfunction

et al. 2009

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This 12-week, multicenter, open-label study assessed the efficacy, pharmacokinetics and safety of a once-daily aliskiren in Japanese hypertensive patients with renal dysfunction. Patients (n¼40, aged 20-80 years) with mean sitting diastolic blood pressure (msDBP) X95 and o110 mm Hg and serum creatinine between X1.3 and o3.0 mg per 100 ml in males or between X1.2 and o3.0 mg per 100 ml in females were eligible. Patients began therapy with a once-daily morning oral dose of 75 mg of aliskiren. In patients with inadequate blood pressure control (msDBP X90 or mean sitting systolic blood pressure [msSBP] X140 mm Hg) and without safety concerns (serum potassium 45.5 mEq l -1 or an increase in serum creatinine X20%), the aliskiren dose was increased to 150 mg and then to 300 mg in sequential steps starting from Week 2. Efficacy was assessed as change in msSBP/msDBP from baseline to the Week 8 endpoint (with the last observation carried forward). The mean reduction from baseline to Week 8 endpoint was 13.9 ± 16.6 and 11.6 ± 9.7 mm Hg for msSBP and msDBP, respectively. At the Week 8 endpoint, 65% patients had achieved blood pressure response (msDBP o90 or a 10 mm Hg decrease or msSBP o140 or a 20 mm Hg decrease) and 30% had achieved blood pressure control (msSBP o140 mm Hg and msDBP o90 mm Hg). Aliskiren was well tolerated with no new safety concerns in Japanese hypertensive patients with renal dysfunction.

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Pharmacokinetics of the Oral Direct??Renin Inhibitor Aliskiren Alone and??in Combination with Irbesartan in??Renal Impairment

Cited by 67 publications

References 24 publications

Effects of Aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension

Effects of Aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension

Aliskiren – an antihypertensive renin inhibitor in the treatment of patients with chronic kidney disease

Efficacy and safety of aliskiren in Japanese hypertensive patients with renal dysfunction

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