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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.
Ang II is formed from Ang I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Ang II is the principal pressor agent of the renin-angiotensin-aldosterone system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of Ang II by selectively blocking the binding of Ang II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for Ang II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200 that of valsartan itself.
Blockade of the renin-angiotensin-aldosterone system with ACE inhibitors, which inhibit the biosynthesis of Ang II from Ang I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the Ang II receptor inhibits the negative regulatory feedback of Ang II on renin secretion, but the resulting increased PRA and Ang II circulating levels do not overcome the effect of valsartan on blood pressure.
Valsartan has indications other than hypertension which can be found in the Diovan® package insert.
Since aliskiren and valsartan block the RAAS at different sites (inhibition of plasma renin activity and antagonism of the AT1 receptor), their combination provides a complementary mechanism to achieve a pharmacologic inhibition of the RAAS. Such RAAS inhibition with Valturna is associated with significant reductions in PRA, Ang I, Ang II and aldosterone.
PRA reductions in clinical trials ranged from approximately 50% to 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.
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.
Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.
In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic blood pressure, usually with little or no orthostatic change.
In normotensive subjects receiving sodium supplementation, a single oral dose of 320 mg valsartan increased PRA, angiotensin I and angiotensin II, whereas 300 mg of aliskiren decreased them for 48 hours. In combination, 150 mg of aliskiren neutralized the 160 mg valsartan-induced increase in PRA, plasma angiotensin I and angiotensin II for 48 hours. The reduction in urinary aldosterone excretion with the 150/160 mg aliskiren/valsartan combination was similar to 300 mg of aliskiren and greater than that of 320 mg of valsartan and placebo.
Absorption and Distribution
Following oral administration of Valturna combination tablets, the median peak plasma concentration times are within 1 hour for aliskiren and 3 hours for valsartan. The mean half-lives of aliskiren and valsartan are 34 hours and 12 hours, respectively. The rate and extent of absorption of aliskiren and valsartan from Valturna are the same as when administered as individual tablets. When taken with food, mean AUC and Cmax of aliskiren are decreased by 76% and 88%, respectively; mean AUC and Cmax of valsartan were not significantly affected. In clinical trials of Valturna, it was administered without requiring a fixed relation of administration to meals.
The steady state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
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 (MDRl/Mdrla/lb) 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.
Valsartan shows bi-exponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP450 enzymes indicated that the CYP2C9 isozyme is responsible for the formation of valeryl-4-hydroxy valsartan. It has also been shown that valsartan does not inhibit CYP450 isozymes at clinically relevant concentrations. CYP450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
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 5 (impact of co-administered drugs on aliskiren) and Figure 6 (impact on co-administered drugs).
Figure 5: The impact of co-administered drugs on the pharmacokinetics
Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.
Figure 6: The impact of aliskiren on the pharmacokinetics
of co-administered drugs.
The pharmacokinetics of Valturna have not been investigated in patients <18 years of age.
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. Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.
With Valturna, pharmacokinetic differences due to race have not been studied. The pharmacokinetic differences among Blacks, Caucasians, and Japanese are minimal with aliskiren therapy.
The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal impairment. 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].
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.
There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis.
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.
On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease.
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 (seven 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.
No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up at 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.
Aliskiren 150 mg and 300 mg and valsartan 160 mg 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 mg 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 statistically significantly (p<0.05) greater than the reductions with the monotherapies as shown in Table 1.
Table 1: Reductions in Seated Trough Cuff Blood Pressure
of Aliskiren in Combination with Valsartan
|0||Placebo-Subtracted Mean Change||--||5.6/3.9p||8.2/5.6p|
|150||Placebo-Subtracted Mean Change||5.4/2.7p||10.0/5.7pav||--|
|300||Placebo-Subtracted Mean Change||8.4/4.9p||--||1 2.6/8. 1pav|
|* 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
pp<0.05 vs. placebo by ANCOVA for the pairwise comparison.
ap<0.05 vs. respective aliskiren monotherapy by ANCOVA for the pairwise comparison.
vp<0.05 vs. respective valsartan monotherapy by ANCOVA for the pairwise comparison.
The safety and efficacy of Valturna as initial therapy were evaluated. The figures [See INDICATIONS] display the probability that a patient will achieve systolic or diastolic blood pressure goal with Valturna 300/320 mg, based upon their baseline systolic or diastolic blood pressure. At all levels of baseline blood pressure, the probability of achieving any given diastolic or systolic goal is greater with the combination than for either monotherapy.
The antihypertensive effect of Valturna was attained within 2 weeks.
One active-controlled trial investigated the addition of aliskiren 300 mg plus valsartan 320 mg in hypertensive patients who did not respond adequately to HCTZ 25 mg, and showed decreases from baseline in systolic and diastolic blood pressure of approximately 22/16 mmHg compared with approximately 6/6 mmHg with continuation of HCTZ 25 mg alone.
The antihypertensive effect was similar in patients with or without diabetes, in patients ≥65 years of age and <65 years of age, and in women and men. The effects of aliskiren, valsartan, and the combination were diminished in Blacks compared to Caucasians as has been seen with ACE inhibitors, other angiotensin receptor blockers, and beta blockers.
There are no trials of the Valturna combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but several ARBs which are the same pharmacological class as the valsartan component, have demonstrated such benefits.
Aliskiren in Patients with Diabetes treated with ARE 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 ARE 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 2: Incidence of selected adverse events in ALTITUDE
| Serious Adverse
| Adverse Events
| Serious Adverse
|†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: 5/7/2012
This monograph has been modified to include the generic and brand name in many instances.
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