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Aliskiren: An orally active renin inhibitor


Pranay Wal, Ankita Wal, Awani K. Rai, and Anuj Dixit
Author information Article notes Copyright and License information
Abstract
High blood pressure (BP) is a prevalent risk factor for cardiovascular disease, affecting more
than 72 million people in India and more than 1 billion people worldwide.[1] The Seventh
Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC 7) recommends a BP treatment goal of <140/90 mmHg for most
patients and <130/80 mmHg for patients with diabetes mellitus (DM) or kidney disease.[1]
Despite the effort of JNC 7 to increase the awareness and treatment of hypertension in the United
States, only 34% of patients with high BP are adequately controlled.[1] Choosing the appropriate
medications for individual patients and adherence to these regimens are among the most
important contributing factors to the success of hypertension control. Of all the different
pharmacological agents that the JNC guidelines recommended for hypertension management,
medications that work by inhibiting the reninangiotensinaldosterone system (RAAS) are
among some of the most commonly prescribed drugs in the United States; these include
angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and
aldosterone antagonists.[2] Not only do these agents help control BP, they have also been found
to reduce cardiovascular events in some disease states.[1] ACE inhibitors and ARBs have been
shown to reduce mortality and recurrent cardiovascular events in patients with heart failure,
myocardial infarction, and previous stroke.[35] In patients with DM or kidney disease, ACE
inhibitors and ARBs also reportedly preserve kidney function in addition to improving
cardiovascular outcomes.[6] Aldosterone antagonists have been found to reduce mortality in
patients with left ventricular dysfunction as well as myocardial infarction.[7] Aliskiren is a firstin-class oral renin inhibitor, developed by Novartis in conjunction with the biotech company
Speedel.[8] It becomes the fourth class of pharmacological agents that modify the function of
RAAS. It is an octanamide, is the first known representative of a new class of completely
nonpeptide, low-molecular-weight, orally active transition-state renin inhibitors. Aliskiren has

good water solubility and low lipophilicity, and is resistant to biodegradation by peptidases in the
intestine, blood circulation, and the liver. Aliskiren provides significant antihypertensive efficacy
in patients with hypertension, with no rebound effects on BP after the withdrawal of the
treatment. Aliskiren has a half-life of approximately 40 h,[9,10] making it suitable for once-daily
dosing, with less potential for loss of efficacy between doses than shorter acting agents.
Continuous 24-h BP control throughout the dosing period is clinically important, as it can reduce
BP variability that may be suboptimally controlled in other drug classes.[1113]

Physiology of the ReninAngiotensinAldosterone


System and hypertension
The RAAS plays a significant role in the pathophysiology of hypertension. The juxtaglomerular
cells in the afferent renal arterioles secrete renin in response to low plasma volume, reduced
renal perfusion, or increased sympathetic central nervous system activity.[14] Renin acts as a
protease enzyme that catalyzes the conversion of angiotensinogen to angiotensin I, which is
subsequently converted to angiotensin II by ACE. Angiotensin II induces adrenal secretion of
aldosterone, which is a mineralocorticoid that leads to sodium and fluid retention, thus increasing
BP. Angiotensin II also has a direct vasoconstrictive effect, which increases BP, and promotes
inflammation and remodeling of the cardiovascular system, which leads to thrombosis or left
ventricular hypertrophy.[15] Renin conversion of angiotensinogen to angiotensin I is the ratelimiting step in angiotensin II formation. Renin is therefore the primary determinant of RAAS
activity.[15] ACE inhibitors hinder the systemic effect of angiotensin II by inhibiting ACE,
which reduces the conversion of angiotensin I to angiotensin II.[16] ARBs directly inhibit the
binding of angiotensin II to the receptor.[17] Aldosterone antagonists inhibit the action of the
excessive aldosterone produced due to increases in angiotensin II.[18] However, both ACE
inhibitors and ARBs can lead to increases in plasma renin activity. With ACE inhibitors, the
angiotensin I level increases and may lead to accessory (i.e., non-ACE pathways) production of
angiotensin II.[19,20] These pathways convert angiotensin I to angiotensin II through alternative
enzymes such as chymase and chymotrypsin-like angiotensin-generating enzyme.[21,22] With
ARBs, angiotensin II levels will increase to compete for receptor bindings. Such increases in
angiotensin II levels may also continue to stimulate release of aldosterone from the adrenal

gland.[21] Research has attempted to improve RAAS inhibition through the combination use of
ACE inhibitors. Aldosterone breakthrough will occur at a far lower frequency during renin
inhibition (010% over 9 months), alone or in combination with an ARB, compared to
conventional ARB therapy (3545% over 9 months). The investigators hypothesize that
aldosterone breakthrough occurs due to accumulation of active precursor substances, most
notably angiotensin II, produced in response to conventional RAAS blockade with ACE
inhibitors and ARBs. The investigators believe that direct renin inhibition (DRI) should minimize
this accumulation and therefore significantly lower or possibly eliminate the breakthrough effect.
Interruption of the RAAS with angiotensin-converting enzyme inhibitors (ACE-Is) and ARBs,
alone and in combination, has become a leading therapy to slow the progression of chronic heart
and kidney disease. Both types of drugs inhibit the formation of aldosterone, a hormone, which
has been shown to have harmful effects on patients with chronic heart and kidney disorders. This
treatment is effective but not perfect since, even after an initial improvement, many patients
become worse over the long term. This may be due to an unexpected increase in aldosterone, a
phenomenon called "aldosterone breakthrough."
The aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) trial[23] was a randomized,
double-blind, placebo-controlled, multinational study that aimed to evaluate the antiproteinuric
effect of aliskiren (300 mg per day) in 599 hypertensive patients with type 2 diabetes and
nephropathy who were on therapy with losartan at a fixed dose of 100 mg per day. The
researchers found that treatment with aliskiren for 24 weeks was associated with a 20% reduction
in albuminuria (compared with no change with placebo). Moreover, a reduction in urinary
albumin:creatinine ratio of 50% or more occurred in 25% of patients on aliskiren compared with
12.5% of patients on placebo. Differences in BP between treatment groups at the end of the study
period were small and not significant, and changes in albuminuria did not correlate with
concomitant changes in arterial BP. These findings led the authors to conclude that aliskiren
might have renoprotective effects that are independent of its blood pressure lowering effects in
patients with hypertension, type 2 diabetes, and nephropathy.[23] The ALiskiren Trial In Type 2
diabetes Using cardio-renal Disease Endpoints (ALTITUDE) study (ClinicalTrials.gov registry
numberNCT00549757) aims to determine whether the addition of aliskiren (300 mg versus
placebo) once daily for 4 years to treatment with ACE inhibitors or ARBs reduces renal and
cardiovascular events in 8600 patients with type 2 diabetes and microalbuminuria,

macroalbuminuria, or cardiovascular disease. A number of other key issues must also be


addressed to determine whether aliskiren is a valuable alternative to currently available RAAS
inhibitors.

Mechanism of Action
Aliskiren exhibits oral bioavailability due to its low molecular weight (609.8 Da) and nonpeptide
structure, making it more resistant to gastrointestinal enzyme disintegration.[24]
Aliskiren is one of the most potent, known renin inhibitors with high specificity for primate
renin.[25]
Aliskiren effectively reduces functional plasma renin activity by binding to renin with high
affinity, preventing it from converting angiotensinogen to angiotensin I.[26,27]
The inhibition of renin by aliskiren is associated with a reduction in circulating levels of
angiotensin I and II, with a resultant increase in plasma renin concentration and inhibit activation
of mitogen-activated protein kinases ERK1 (p44) and ERK2 (p42).[27,28]
It prevents hypertrophy and proliferation.

Chemical Properties
Aliskiren is a low-molecular-weight hydrophilic nonpeptide, which exerts a potent and specific
competitive inhibition on renin in primates. The adverse effects of aliskiren are uncertain due to
its 10,000-fold higher affinity for renin than for other aspartic peptidases. Because renin is a
water-soluble protein that can be studied with crystallographic analysis, the opportunity arose to
examine systematically the crystals of renin bond to renin inhibitors. Aliskiren is a transitionstate mimetic, with favorable physicochemical properties including high aqueous solubility
(>350 mg/ml at pH 7.4) and high hydrophilicity (log Poct/water = 2.45, pH 7.4). These
properties are important prerequisites for improved oral bioavailability.[29]

Pharmacokinetics

Aliskiren is also metabolized by cytochrome P450 (CYP) 3A4 enzymes, but the exact extent of
metabolism is unknown.[26,27,30,31] Although aliskiren exhibits oral bioavailability compared
with other previously synthesized renin inhibitors, it is still poorly absorbed (oral bioavailability,
2.5%).[32] In nine healthy volunteers aged 2034 years, after administration of oral aliskiren
40640 mg daily, the plasma concentration exhibited dose-dependent increases, with peak
concentrations achieved after 36 h of administration.[26] Aliskiren is 50% protein bound, and
the apparent volume of distribution is 135 L.[31] The pharmacokinetics of aliskiren remains
unaffected by ethnicity, age, gender, hepatic impairment, renal impairment, and diabetes.[32] The
elimination t1/2 of aliskiren averaged 24 h (2045 h) in healthy volunteers as well as in patients
with DM. Plasma steady-state concentrations are therefore achieved in approximately 58 days
(five times the half-life). This relatively long half-life makes aliskiren suitable for QD dosing.
Peak plasma concentrations are reached 12 h after dosing, and steady state is reached after 58
days of once-daily administration.[27,28] Conventional pharmacokinetic studies have been
performed in rats, marmosets, and humans after single and multiple oral doses of aliskiren.
Aliskiren shows low bioavailability, but the exact mechanism of this property has not been
elucidated. The distribution volume of intravenously administered aliskiren is reported to be 135
L, in normal volunteers, indicating extensive tissue uptake of the drug. Aliskiren binds only
moderately to plasma proteins, with the binding concentrations being independent in the range of
10500 ng/ml. Approximately 4751% of aliskiren is bound by plasma proteins in humans,
independent of the concentration. In marmosets, aliskiren is highly bound to plasma proteins by
approximately 92%.[27] Aliskiren is slightly metabolized in humans (about 20%) and is
approximately 50% metabolized in rodents. The major metabolic pathway for aliskiren
metabolism is O-demethylation at the phenyl-proxy side chain or at the 3-methoxypropoxy
group, with further oxidation to the carboxylic acid derivative. The metabolism of aliskiren
observed in liver microsomes is qualitatively comparable in humans, marmosets, and rats.[27,31]
The main pathway of elimination for aliskiren is via biliary excretion as unmetabolized drug.
Less than 1% of an orally administered dose is excreted in urine.[33] Aliskiren is not
metabolized by, and does not induce or inhibit, cytochrome P450 enzymes and shows no
clinically relevant pharmacokinetic interactions with warfarin, lovastatin, atenolol, celecoxib,
cimetidine, amlodipine, valsartan, hydrochlorothiazide (HCTZ), or ramipril. Coadministration of
aliskiren with furosemide reduced the AUC of furosemide by 28% and C max by 49%, but clinical

significance of this remains uncertain. Aliskiren pharmacokinetics has been studied in


marmosets. After a single oral dose of 10 mg/kg, peak plasma concentrations were reached in 1
2 h. The calculated bioavailability was 16.3% and mean half-life 2.3 h.[34] Aliskiren
accumulates following multiple once-daily administrations as indicated by the accumulation
ratios of 1.43.9, with the accumulation being more pronounced at higher doses. Study in healthy
volunteers showed that the plasma concentration increased dose-dependently after oral aliskiren
in doses of 40640 mg/day, with peak plasma concentrations reached in 36 h. The mean plasma
half-life was 23.7 h.

Drug Interactions
Effects of other drugs on aliskiren
Based on in vitro studies, aliskiren is metabolized by CYP 3A4.
Irbesartan: Coadministration of irbesartan reduced aliskiren Cmax up to 50% after multiple dosing.
P-glycoprotein Effects: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system
involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug
interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.
Atorvastatin: Coadministration of atorvastatin resulted in about a 50% increase in aliskiren
Cmax and AUC after multiple dosing.
Ketoconazole: Coadministration of 200 mg twice-daily ketoconazole with aliskiren resulted in an
approximate 80% increase in plasma levels of aliskiren. A 400-mg once-daily dose was not
studied but would be expected to increase aliskiren blood levels further.
Itraconazole: Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in
approximately 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren. Concomitant
use of aliskiren with itraconazole is not recommended.
Cyclosporine: Coadministration of 200 and 600 mg cyclosporine with 75 mg aliskiren resulted in
an approximately 2.5-fold increase in C max and fivefold increase in AUC of aliskiren.
Concomitant use of aliskiren with cyclosporine is not recommended.

Verapamil: Coadministration of 240 mg of verapamil with 300 mg aliskiren resulted in an


approximately twofold increase in Cmax and AUC of aliskiren. However, no dosage adjustment is
necessary.
Drugs with no clinically significant effects: Coadministration of lovastatin, atenolol, warfarin,
furosemide, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin, and
amlodipine did not result in clinically significant increases in aliskiren exposure.
Adverse events, contraindications, and precautions for aliskiren
Aliskiren has been shown to be well tolerated in healthy subjects and in patients with
hypertension, when given as single and multiple oral doses. The clinical trials do not report any
major adverse effects of aliskiren. Aliskiren-based therapy was well tolerated and produced
sustained BP reductions in patients with hypertension during 6 months, greater than those with
ramipril-based therapy. The incidence of adverse events with aliskiren and the number of study
discontinuations as a result of adverse events during aliskiren treatment have been relatively low
and were similar to results obtained in patients treated with placebo. The most commonly
reported adverse events included headache, dizziness, and fatigue (incidence ranged from 2.4%
to 8.5% among studies).[33,3542] Aliskiren is also associated with dose-related gastrointestinal
adverse events. Although the incidence of diarrhea reported with aliskiren up to 300 mg daily did
not differ significantly from placebo, when aliskiren 600 mg daily was administered in one study,
the incidence of diarrhea was significantly higher than that of placebo (11.4% vs 0.2%; P <
0.001).[35] Aliskiren use was associated with a slight increase in cough in placebo-controlled
studies (1.1% for any aliskiren use vs 0.6% for placebo).[35,36,39] In studies comparing
aliskiren and ACE inhibitors, the rates of cough for aliskiren were about one-third to one-half the
rates of ACE inhibitors. Hyperkalemia was reported infrequently in aliskiren use (0.9% vs
0.6% in placebo). However, when used in combination with an ACE inhibitor, hyperkalemia
occurred more frequently (5.5%).[43] Aliskiren had no clinically important effects on total
cholesterol, HDL, fasting triglycerides, or fasting glucose. Laboratory abnormalities that may
occur in some patients include a minor increase in blood urea nitrogen (BUN) and serum
creatinine, small reductions in hemoglobin and hematocrit, an increase in serum potassium
greater than 5.5 mEq/L, elevated uric acid levels, and renal stones.

Dosage and Administration


Aliskiren is available in 150- and 300-mg tablets. The usual recommended starting dose of
aliskiren is 150 mg QD. Doses >300 mg did not provide an increased BP response but did
increase the rate of diarrhea by approximately threefold in one study. The antihypertensive effect
of a given dose of aliskiren is attained after 2 weeks of therapy.[44] No dosage adjustment is
required when used in elderly patients (i.e., those aged >65 years) or those with mild to severe
renal impairment (creatinine clearance, <80 mL/min) or hepatic impairment (Child-Pugh Clinical
Assessment score, 515).[45]

Future Perspectives
Medications that have direct effects on the RAAS, such as ACE inhibitors, ARBs, and
aldosterone antagonists, have been found to not only effectively lower BP but also to improve
mortality and morbidity in patients with heart failure (ACE inhibitors, ARBs, and aldosterone
antagonists), history of myocardial infarction (ACE inhibitors, ARBs, and aldosterone
antagonists), and nephropathy (ACE inhibitors and ARBs). Aliskiren directly inhibits renin and,
from a mechanism of action point of view, offers an advantage over ACE inhibitors and ARBs by
inhibiting the rate-limiting step of angiotensin II formation and producing more effective and
complete inhibition of angiotensin II. Whether such effects result in better protection from heart
attack, stroke, myocardial infarction, and nephropathy is unknown. Whether the additive benefit
in hypertension with the combination of aliskiren and ACE inhibitors or ARBs will extend to
other indications is also unknown. Furthermore, it is not known whether patients who cannot
tolerate ACE inhibitors or ARBs can be safely switched to aliskiren. Further research
investigating these potential roles will help establish a place for aliskiren in cardiovascular
disease management. There are ongoing studies evaluating the use of aliskiren in patients with
postmyocardial infarction as well as in those with diabetic nephropathy.[46]

Conclusions

Aliskiren is an orally effective, long-lasting renin inhibitor that shows antihypertensive efficacy
in animals superior to previous renin inhibitors and at least equivalent to ACE inhibitors and AT1receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment
of hypertension and related disorders, alone or in combination with other antihypertensive
agents.[34] Aliskiren is well tolerated, with the most common adverse events reported as
headache, dizziness, and fatigue. Clinical studies support the use of aliskiren in patients with
mild to moderate hypertension, alone or in combination with ACE inhibitors, amlodipine, or
diuretics. Future studies will provide more insights into the long-term effects of the use of renin
inhibitors in hypertension treatment, as well as whether such treatment may alter cardiovascular
outcomes.

Footnotes
Source of Support: Nil
Conflict of Interest: None declared

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