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
Based on in-vitro studies, aliskiren is metabolized by CYP 3A4.
Co-administration of lovastatin, atenolol, warfarin, furosemide, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin and amlodipine did not result in clinically significant increases in aliskiren exposure.
Co-administration 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.
Co-administration of aliskiren with Pgp substrates or weak to moderate inhibitors
such as atenolol, digoxin, and amlodipine did not result in clinically relevant
interactions.
Co-administration of atorvastatin, a potent Pgp inhibitor, resulted in about
a 50% increase in aliskiren Cmax and AUC after multiple dosing.
Ketoconazole
Co-administration of 200 mg twice-daily ketoconazole, a potent Pgp inhibitor, 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.
Cyclosporine
Co-administration of 200 mg and 600 mg cyclosporine, a highly potent Pgp inhibitor,
with 75 mg aliskiren resulted in an approximately 2.5 fold increase in Cmax
and 5 fold increase in AUC of aliskiren. Concomitant use of aliskiren with cyclosporine
is not recommended.
Effects of Aliskiren on Other Drugs
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP 3A) or induce CYP 3A4.
Co-administration of aliskiren did not significantly affect the pharmacokinetics
of lovastatin, digoxin, valsartan, amlodipine, metformin, celecoxib, atenolol,
atorvastatin, ramipril or hydrochlorothiazide.
Warfarin
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated in a well-controlled clinical trial.
Furosemide
When aliskiren was co-administered with furosemide, the AUC and Cmax of furosemide
were reduced by about 30% and 50%, respectively.
Clinical Trials
Aliskiren Monotherapy
The antihypertensive effects of Tekturna® (aliskiren) have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 1.
Table 1: Reductions in Seated Trough Cuff Blood Pressure
in the Placebo-Controlled Studies
| |
|
Aliskiren daily dose, mg |
| Study |
Placebo |
75 |
150 |
300 |
600 |
| |
Mean change |
Placebo- subtracted |
Placebo- subtracted |
Placebo- subtracted |
Placebo- subtracted |
| 1 |
2.9/3.3 |
5.7/4* |
5.9/4.5* |
11.2/7.5* |
-- |
| 2 |
5.3/6.3 |
-- |
6.1/2.9* |
10.5/5.4* |
10.4/5.2* |
| 3 |
10/8.6 |
2.2/1.7 |
2.1/1.7 |
5.1/3.7* |
-- |
| 4 |
7.5/6.9 |
1.9/1.8 |
4.8/2* |
8.3/3.3* |
-- |
| 5 |
3.8/4.9 |
-- |
9.3/5.4* |
10.9/6.2* |
12.1/7.6* |
| 6 |
4.6/4.1 |
-- |
-- |
8.4/4.9† |
-- |
*p < 0.05 vs. placebo by ANCOVA with Dunnett's procedure
for multiple comparisons.
†p < 0.05 vs. placebo by ANCOVA for the pairwise comparison. |
The studies included approximately 2,730 patients given doses of 75-600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increase at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment. Studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP ranged from 0.6 to 0.9.
Patients in the placebo-controlled trials continued open-label aliskiren for
up to one year. A persistent blood pressure lowering effect was demonstrated
by a randomized withdrawal study (patients randomized to continued drug or placebo),
which showed a statistically significant difference between patients kept on
aliskiren and those randomized to placebo. With cessation of treatment, blood
pressure gradually returned toward baseline levels over a period of several
weeks. There was no evidence of rebound hypertension after abrupt cessation
of therapy.
Aliskiren lowered blood pressure in all demographic subgroups, although Black
patients tended to have smaller reductions than Caucasians and Asians, as has
been seen with ACE inhibitors and ARBs.
Aliskiren in Combination with Other Antihypertensives
Diuretics
Aliskiren 75, 150, and 300 mg and hydrochlorothiazide 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 2.
Table 2: Placebo-Subtracted Reductions in Seated Trough Cuff
Blood Pressure in Combination with Hydrochlorothiazide
| |
|
Hydrochlorothiazide, mg |
| Aliskiren, mg |
Placebo mean change |
0 |
6.25 |
12.5 |
25 |
| Placebo- subtracted |
Placebo- subtracted |
Placebo- subtracted |
Placebo- subtracted |
| 0 |
7.5/6.9 |
-- |
3.5/2.1 |
6.4/3.2 |
6.8/2.4 |
| 75 |
-- |
1.9/1.8 |
6.8/3.8 |
8.2/4.2 |
9.8/4.5 |
| 150 |
-- |
4.8/2 |
7.8/3.4 |
10.1/5 |
12/5.7 |
| 300 |
-- |
8.3/3.3 |
-- |
12.3/7 |
13.7/7.3 |
Valsartan
Aliskiren 150 and 300 mg and valsartan 160 and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3.
Table 3: Placebo-Subtracted Reductions in Seated Trough Cuff
Blood Pressure in Combination with Valsartan
| Aliskiren, mg |
Placebo mean change |
Valsartan, mg |
| 0 |
160 |
320 |
| 0 |
4.6/4.1* |
-- |
5.6/3.9 |
8.2/5.6 |
| 150 |
-- |
5.4/2.7 |
10.0/5.7 |
-- |
| 300 |
-- |
8.4/4.9 |
-- |
12.6/8.1 |
| * The placebo change is 5.2/4.8 for week 4 endpoint which
was used for the dose groups containing Aliskiren 150 mg or Valsartan 160
mg. |
ACE inhibitors and Amlodipine
Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction with a maximal dose of an ACE inhibitor. Aliskiren 150 mg provided additional blood pressure reduction when co-administered with amlodipine 5 mg in one study, but the combination was not statistically significantly better than amlodipine 10 mg.
Last updated on RxList: 8/18/2008