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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.
In placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 50- 80%. This reduction in PRA was not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.
Aliskiren is poorly absorbed (bioavailability about 2.5%) 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 – 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. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP 3A4.
Transporters: 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.
The effect of co-administered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on aliskiren) and Figure 2 (impact of aliskiren on co-administered drugs).
Figure 1: The impact of co-administered drugs on the
pharmacokinetics of aliskiren
Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.
Figure 2: The impact of aliskiren on the
pharmacokinetics of co-administered drugs
Furosemide: In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day.
Renally Impaired Patients: Aliskiren was evaluated in patients with varying degrees of renal insufficiency. The 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 WARNINGS AND PRECAUTIONS].
The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis was not clinically significant.
Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis.
Hepatically Impaired Patients: 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.
Pediatric Patients: The pharmacokinetics of aliskiren have not been investigated in patients < 18 years of age.
Geriatric Patients: Exposure (measured by AUC) is increased in elderly patients ≥ 65 years. Adjustment of the starting dose is not required in these patients.
Race: The pharmacokinetic differences between Blacks, Caucasians, and the Japanese are minimal.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose (MRHD) of 300 mg/day on a mg/m² basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m² basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m² basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits.
The antihypertensive effects of Tekturna have been demonstrated in six randomized, double-blind, placebo-controlled 8week 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
|Study||Placebo mean change||Aliskiren daily dose, mg|
|*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 increases 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 range 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 continue 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 reduction than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs.
There are no studies of Tekturna or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.
Aliskiren in Combination with Other Antihypertensives
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
|Aliskiren, mg||Placebo mean change||Hydrochlorothiazide, mg|
Aliskiren 150 and 300 mg and valsartan 160 and 320 mg were studied alone and in combination in an 8-week, 1,797patient, 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|
|* 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.|
Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4.
Table 4: Placebo-Subtracted
Reductions in Seated Trough Cuff Blood Pressure in Combination with Amlodipine
|Aliskiren, mg||Placebo mean change||Amlodipine, mg|
Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction.
Aliskiren in Patients with Diabetes treated with ARB or ACEI (ALTITUDE study)
Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4283) or placebo (n=4296). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month. After a median follow up of about 27 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the table below.
Table 5: Incidence of
selected adverse events in ALTITUDE
|Serious Adverse Events* (%)||Adverse Events (%)||Serious Adverse Events* (%)||Adverse Events (%)|
|Renal impairment †||4.7||12.4||3.3||10.4|
|†renal failure, renal failure
acute, renal failure chronic, renal impairment
††dizziness, dizziness postural, hypotension, orthostatic hypotension, presyncope, syncope
††† Given the variable baseline potassium levels of patients with renal insufficiency on dual RAAS therapy, the reporting of adverse event of hyperkalemia was at the discretion of the investigator.
* A Serious Adverse Event (SAE) is defined as: an event which is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization, or is medically significant (i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes previously listed).
The risk of stroke (2.7% aliskiren vs 2.0% placebo) and death (6.9% aliskiren vs. 6.4% placebo) were also numerically higher in aliskiren treated patients.
Last reviewed on RxList: 11/15/2013
This monograph has been modified to include the generic and brand name in many instances.
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