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Aliskiren
See also Renin inhibitors, direct
General information
Aliskiren is an orally active, non-peptidic inhibitor of renin, and is the only direct renin inhibitor approved for the treatment of hypertension. Its potential adverse effects and a comparison with other renin–angiotensin blockers have been reviewed [ ].
Aliskiren is a novel compound that was developed by the use of X-ray crystallography of the active site of renin and subsequent computational modelling. Its non-peptide structure overcame some of the difficulties of previous attempts at producing renin inhibitors, although it still has some interesting pharmacokinetic properties. It is the first in class of the orally active, non-peptide, direct renin inhibitors for the treatment of hypertension to go into phase III trials.
The adverse effects of renin inhibitors compared with other renin–angiotensin blockers have been reviewed [ ]. The renin inhibitors should lack the effects of ACE inhibitors that are mediated through the accumulation of substance P, bradykinin, and other peptides, such as dry cough and angioedema. Aliskiren has been purported in trials to have “placebo-like” tolerability and a safety profile equivalent to that of angiotensin receptor antagonists [ ]. The most common adverse effects reported in the trials to date have been headache, diarrhea, and dizziness, all at low incidence rates.
The systemic availability of aliskiren is limited, less than 3% of the parent compound being absorbed. Its half-life is in the region of 40 hours, which allows effective once-daily dosing; steady-state plasma concentrations are achieved after 5–8 days [ ]. Aliskiren has little clinically significant interaction with cytochrome P450 liver enzymes and no significant hepatic metabolism. Mild to severe hepatic impairment had no significant effect on the single-dose pharmacokinetics of aliskiren [ ]. The main route of elimination is biliary excretion and consequent fecal elimination. Renal clearance plays a minor role, about 1% being excreted in the urine. Aliskiren is a substrate for P glycoprotein and co-administration of other drugs that interfere with P glycoprotein could theoretically alter exposure to aliskiren; however, in elderly patients (65 years and over) there were only modest increases in drug exposure [ ].
In healthy volunteers aliskiren produces dose-dependent reductions in plasma renin activity and angiotensin I and angiotensin II concentrations [ ], which translates into effective blood pressure lowering.
Drug studies
Comparative studies
The favorable effect of aliskiren on plasma renin activity implies that combination treatment with antihypertensive agents that otherwise increase renin activity should be beneficial. Aliskiren has been investigated in open studies in combination with hydrochlorothiazide, ramipril, and irbesartan [ ]. Plasma renin activity did not increase compared with baseline, which suggests that combination therapy can achieve increased renin–angiotensin system suppression and improved blood pressure control.
In a comparison of aliskiren and ramipril, alone or in combination, the incidence of cough with aliskiren was lower than with ramipril, but the incidence with the combination was, surprisingly, lower still [ ]. Combination treatment with calcium channel blockers may also reduce the incidence of edema seen with agents such as amlodipine and provide an advantage to this combination. In a comparison of the combined use of aliskiren and valsartan against both agents alone or placebo in 1979 patients with hypertension the combination produced significantly greater reductions in blood pressure than either agent alone [ ].
Placebo-controlled studies
The largest clinical studies with aliskiren have investigated the use of doses of up to 600 mg/day and have shown effective blood pressure lowering in patients with hypertension. In an 8-week study in 652 patients, aliskiren (150, 300, and 600 mg) was compared with placebo and irbesartan [ ]. Aliskiren 150 mg was as effective as irbesartan 150 mg, while higher doses lowered mean sitting diastolic blood pressure significantly more. The incidences of adverse events were comparable with aliskiren, irbesartan, and placebo.
In an 8-week placebo-controlled study in 672 hypertensive patients, aliskiren 150–600 mg/day was significantly superior to placebo in lowering mean sitting systolic and diastolic blood pressures at all doses; maximal or near-maximal reductions were achieved by week 4 [ ]. In a subgroup of patients evaluated with ambulatory blood pressure monitoring, the blood pressure lowering effect was sustained throughout the 24-hour dosing interval. There are many more clinical studies in progress or soon to be published.
Two more reviews of the clinical pharmacology of aliskiren [ ] and trials of its effects [ ] have been published. Its antihypertensive efficacy and tolerability at doses of 150, 300, and 600 mg/day compared with placebo over 8 weeks have been evaluated in a dose-ranging study [ ]. The most frequent adverse effects were headache and nasopharyngitis, and diarrhea was increased in incidence at the highest dose. These effects, and the specific high-dose effect of diarrhea, are similar to those seen in previous studies of aliskiren.
Organs and systems
Cardiovascular
The renin–angiotensin system plays a central role in hypertension, mediating its effects through the peptide hormone angiotensin II, which increases arterial tone, stimulates aldosterone release, activates sympathetic neurotransmission, and promotes renal sodium reabsorption. Overactivation of the renin–angiotensin system therefore contributes to hypertension and its associated end-organ damage. The system can be inhibited at various points: ACE inhibitors reduce the conversion of angiotensin I to angiotensin II and angiotensin II receptor blockers antagonize the interaction of angiotensin II with the type-1 angiotensin II (AT1) receptor. However, both of these classes of agent interfere with the normal feedback mechanism to the juxtaglomerular apparatus in the kidneys and thus lead to a reactive rise in plasma renin activity, which can partially counteract their effects. Optimal blockade of the renin–angiotensin–aldosterone system should therefore be achievable by blocking the proximal step in the conversion of angiotensinogen to angiotensin I by directly inhibiting the action of renin, thus attenuating the reactive rise in plasma renin activity.
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