Mechanism of Action

Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known. All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. PRA reductions in clinical trials ranged from approximately 50%-80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

Pharmacokinetics

Aliskiren is a poorly absorbed (bioavailability about 2.5%) drug with an approximate accumulation half life of 24 hours. Steady-state blood levels are reached in about 7-8 days.

Absorption and Distribution

Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85%, respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals.

Metabolism and Elimination

About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP 3A4.

Special Populations

Pediatric

The pharmacokinetics of aliskiren have not been investigated in patients < 18 years of age.

Geriatric

The pharmacokinetics of aliskiren were studied in the elderly ( ≥ 65 years). Exposure (measured by AUC) is increased in elderly patients. Adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).

Race

The pharmacokinetic differences between Blacks, Caucasians and the Japanese are minimal.

Renal Insufficiency

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to- severe liver disease. Consequently, adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).

Cardiac Electrophysiology

Aliskiren's effects on ECG intervals were studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12-lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen.

Drug Interactions

Effects of Other Drugs on Aliskiren

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