Tareg Mechanism of Action

Pharmacotherapeutic group: Angiotensin II antagonists, plain. ATC code: C09CA03.
Pharmacology: Pharmacodynamics: The active hormone of the RAAS is angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.
Valsartan is an orally active, potent, and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT₁ receptor blockade with valsartan may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the AT₁ receptor. Valsartan does not exhibit any partial agonist activity at the AT₁ receptor and has much (about 20,000 fold) greater affinity for the AT₁ receptor than for the AT₂ receptor.
Valsartan does not inhibit ACE (also known as kininase II) which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough.
In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P<0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Clinical Studies: Hypertension: Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In multiple dose studies in hypertensive patients valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Heart Failure: Hemodynamics and neurohormones: Hemodynamics and plasma neurohormones were measured in NYHA class II-IV heart failure patients with pulmonary capillary wedge pressure >15 mmHg in 2 short-term, chronic therapy studies. In one study, which included patients chronically treated with ACE inhibitors, single and multiple doses of valsartan given in combination with an ACE inhibitor improved hemodynamics including pulmonary capillary wedge pressure (PCWP), pulmonary artery diastolic pressure (PAD) and systolic blood pressure (SBP). Reductions were observed in plasma aldosterone (PA) and plasma noradrenalin (PNE) levels after 28 days of treatment. In the second study, which included only patients untreated with ACE inhibitors for at least 6 months prior to enrolment, valsartan significantly improved PCWP, systemic vascular resistance (SVR), cardiac output (CO) and SBP after 28 days of treatment. In the long-term Val-HeFT study, plasma noradrenalin and brain natriuretic peptide (BNP) were significantly reduced from baseline in the valsartan group compared to placebo.
Morbidity and mortality: Val-HeFT was a randomized, controlled, multinational clinical trial of valsartan compared with placebo on morbidity and mortality in NYHA class II (62%), III (36%) and IV (2%) heart failure patients receiving usual therapy with LVEF < 40% and left ventricular internal diastolic diameter (LVIDD) >2.9 cm/m². The study enrolled 5,010 patients in 16 countries who were randomized to receive either valsartan or placebo in addition to all other appropriate therapy including ACE inhibitors (93%), diuretics (86%), digoxin (67%) and beta-blockers (36%). The mean duration of follow-up was nearly two years. The mean daily dose of valsartan in Val-HeFT was 254 mg. The study had 2 primary endpoints: all-cause mortality (time to death) and heart failure morbidity (time to first morbid event) defined as death, sudden death with resuscitation, hospitalization for heart failure, or administration of intravenous inotropic or vasodilator drugs for four hours or more without hospitalization. All-cause mortality was similar in the valsartan and placebo groups. Morbidity was significantly reduced by 13.2% with valsartan compared with placebo. The primary benefit was a 27.5% reduction in risk for time to first heart failure hospitalization. The benefits were greatest in patients not receiving either an ACE inhibitor or a beta-blocker. However, risk reductions favoring placebo were observed for those patients treated with the triple combination of a beta-blocker, an ACE inhibitor and valsartan. Further studies such as VALIANT (see Post-myocardial infarction as follows), where mortality was not increased in these patients, have reduced the concerns regarding the triple combination.
Exercise tolerance and capacity: The effects of valsartan in addition to usual heart failure therapy on exercise tolerance using the Modified Naughton Protocol were measured in NYHA class II-IV heart failure patients with left ventricular dysfunction (LVEF ≤40%). Increased exercise time from baseline was observed for all treatment groups. Greater mean increases from baseline in exercise time were observed for the valsartan groups compared to the placebo group, although statistical significance was not achieved. The greatest improvements were observed in the subgroup of patients not receiving ACE inhibitor therapy where mean changes in exercise time were two times greater for the valsartan groups compared to the placebo group. The effects of valsartan compared to enalapril on exercise capacity using the six minute walk test were determined in NYHA class II and III heart failure patients with left ventricular ejection fraction ≤45% who had been receiving ACE inhibitor therapy for at least 3 months prior to study entry. Valsartan 80 mg to 160 mg once daily was at least as effective as enalapril 5 mg to 10 mg twice daily, with respect to exercise capacity, as measured by the six minute walk test in patients previously stabilized on ACE inhibitors and directly switched to valsartan or enalapril.
NYHA class, signs and symptoms, quality of life, ejection fraction: In Val-HeFT, valsartan treated patients showed significant improvement in NYHA class, and heart failure signs and symptoms, including dyspnoea, fatigue, edema and rales compared to placebo. Patients on valsartan had a better quality of life as demonstrated by change in the Minnesota Living with Heart Failure Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan treated patients was significantly increased and LVIDD significantly reduced from baseline at endpoint compared to placebo.
Post-myocardial infarction: The VALsartan In Acute myocardial iNfarction trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive heart failure and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 mg twice daily to highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor captopril (titrated from 6.25 mg three times daily to highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The mean treatment duration was two years. The mean daily dose of valsartan in the monotherapy group was 217 mg. Baseline therapy included acetylsalicylic acid (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%), and statins (34%). The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. The primary endpoint was time to all-cause mortality.
Valsartan was at least as effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the valsartan (19.9%), captopril (19.5%), and valsartan + captopril (19.3%) groups. Valsartan was also effective in prolonging the time to and reducing cardiovascular mortality, hospitalization for heart failure, recurrent myocardial infarction, resuscitated cardiac arrest, and non-fatal stroke (secondary composite endpoint).
Since this was a trial with an active control (captopril), an additional analysis of all-cause mortality was performed to estimate how valsartan would have performed versus placebo. Using the results of the previous reference myocardial infarction trials - SAVE, AIRE, and TRACE - the estimated effect of valsartan preserved 99.6% of the effect of captopril (97.5% CI=60-139%). Combining valsartan with captopril did not add further benefit over captopril alone. There was no difference in all-cause mortality based on age, gender, race, baseline therapies or underlying disease.
There was no difference in all-cause mortality or cardiovascular mortality or morbidity when beta-blockers were administered together with the combination of valsartan + captopril, valsartan alone, or captopril alone. Irrespective of study drug treatment, mortality was higher in the group of patients not treated with a beta-blocker, suggesting that the known beta blocker benefit in this population was maintained in this trial. In addition, the treatment benefits of the combination of valsartan + captopril, valsartan monotherapy, and captopril monotherapy were maintained in patients treated with beta-blockers.
Hypertensive adult patients with Impaired Glucose Tolerance at cardiovascular risk: The Nateglinide And Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial was a multinational, double-blind, placebo-controlled, forced-titration 2x2 factorial design study in which 9,306 patients with impaired glucose tolerance at cardiovascular risk were randomized to placebo, valsartan (titrated from 80 mg once daily to 160 mg once daily, as tolerated), nateglinide (a D-phenylalanine derivative with insulinotropic activity) or nateglinide + valsartan, in addition to lifestyle modification. Patients were followed for a median of about 5 years for the development of diabetes. The population studied was 49% male, 43% 65 years or older and 83% Caucasian. The most commonly reported cardiovascular risk factors at baseline included hypertension (78%) and dyslipidemia (45%) with the majority of these patients receiving antihypertensive and lipid lowering therapy, respectively. Established cardiovascular disease was present in 24% of patients with the most common diagnoses being previous myocardial infarction (12%) and angina with documented multivessel coronary artery disease (9%). During the study, lipid lowering agents were used by 56% of patients and anti-thrombotic agents by 55% of patients.
There were three co-primary endpoints: Development of diabetes; extended composite cardiovascular endpoint (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization or hospitalization for unstable angina); core composite cardiovascular endpoint that excluded unstable angina and arterial revascularization.
There was a statistically significant 14% reduction in the risk of progression to diabetes in valsartan-treated patients also receiving lifestyle intervention measures. However, there was a neutral effect on the core and extended cardiovascular endpoints. These effects were consistent in the large subgroup of patients with hypertension and also across subgroups defined by age, gender, and race. The number of black patients was small and results in this subgroup should be viewed with caution.
There also was a significant reduction in risk of the development of microalbuminuria in valsartan-treated patients compared to non-valsartan treated patients [5.8% vs. 8.4%; HR 0.68; 95% CI (0.573, 0.800); p <0.0001].
Pediatric population (Hypertension): The antihypertensive effect of valsartan has been evaluated in four randomized, double-blind clinical studies in 561 pediatric patients from 6 to 18 years of age and 165 pediatric patients 1 to 6 years of age. Renal and urinary disorders and obesity were the most common underlying medical conditions potentially contributing to hypertension in the children and adolescents enrolled in these studies.
Clinical experience in children and adolescents at or above 6 years of age: In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <35 kg received 10, 40 or 80 mg of valsartan tablets daily (low, medium and high doses), and patients who weighed ≥35 kg received 20, 80, and 160 mg of valsartan tablets daily (low, medium and high doses). At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by 8, 10, 12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mmHg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.
In another clinical study involving 300 hypertensive pediatric patients 6 to 18 years of age, eligible patients were randomized to receive valsartan or enalapril tablets for 12 weeks. Children weighing between ≥18 kg and <35 kg received valsartan 80 mg or enalapril 10 mg; those between ≥35 kg and <80 kg received valsartan 160 mg or enalapril 20 mg; those ≥80 kg received valsartan 320 mg or enalapril 40 mg. Reductions in systolic blood pressure were comparable in patients receiving valsartan (15 mmHg) and enalapril (14 mmHg) (non-inferiority p-value <0.0001). Consistent results were observed for diastolic blood pressure with reductions of 9.1 mmHg and 8.5 mmHg with valsartan and enalapril, respectively.
Clinical experience in children less than 6 years of age: Two clinical studies were conducted in patients aged 1 to 6 years with 90 and 75 patients, respectively. No children below the age of 1 year were enrolled in these studies. In the first study, the efficacy of valsartan was confirmed compared to placebo but a dose-response could not be demonstrated. In the second study, higher doses of valsartan were associated with greater BP reductions, but the dose response trend did not achieve statistical significance and the treatment difference compared to placebo was not significant. Because of these inconsistencies, valsartan is not recommended in this age group (see Adverse Reactions).
Pharmacokinetics: Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. When valsartan is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hours post dosing, plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution: Steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t_1/2α<1 h and t_1/2β about 9 h). Valsartan is primarily eliminated in feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. 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 half-life of valsartan is 6 hours.
The pharmacokinetics of valsartan are linear in the dose range tested. There is no change in the kinetics of valsartan on repeated administration, and little accumulation when dosed once daily. Plasma concentrations were observed to be similar in males and females.
The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to that observed in healthy volunteers. AUC and C_max values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
Special populations: Geriatric patients (aged 65 years or above): A somewhat higher systemic exposure to valsartan was observed in some elderly subjects compared to young subjects; however, this has not been shown to have any clinical significance.
Impaired renal function: As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Dose adjustment is therefore not required in patients with renal impairment. No studies have been performed in patients undergoing dialysis. However, valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic impairment: About 70% of the absorbed dose is excreted in the bile mainly as unchanged compound. Valsartan does not undergo extensive biotransformation and, as expected, systemic exposure to valsartan is not correlated with the degree of liver dysfunction. No dose adjustment for valsartan is therefore necessary in patients with hepatic insufficiency of non-biliary origin and without cholestasis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction (see Precautions).
Pediatric population: In a study of 26 pediatric hypertensive patients (aged 1 to 16 years) given a single dose of a suspension of valsartan (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the clearance (litres/h/kg) of valsartan was comparable across the age range of 1 to 16 years and similar to that of adults receiving the same formulation (see Use in Children under Precautions).
Toxicology: Preclinical Safety Data: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential and effects on fertility.
Safety pharmacology and Long term toxicity: In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan in humans.
In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg/day body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy including raised blood urea nitrogen and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Reproductive toxicity: In a rat fertility study, valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, approximately 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
Mutagenicity: Valsartan was devoid of mutagenic potential at either the gene or chromosome level when investigated in various standard in vitro and in vivo genotoxicity studies.
Carcinogenicity: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for 2 years at doses up to 160 and 200 mg/kg/day, respectively.
Pediatric population: Daily oral dosing of neonatal/juvenile rats (from a postnatal day 7 to postnatal day 70) with valsartan at doses as low as 1 mg/kg/day (about 10-35% of the maximum recommended pediatric dose of approximately 4 mg/kg/day on systemic exposure basis) produced persistent, irreversible kidney damage. These effects mentioned previously represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. The rats in the juvenile valsartan study were dosed up to day 70, and effects on renal maturation (postnatal 4-6 weeks) cannot be excluded. Functional renal maturation is an ongoing process within the first year of life in humans. Consequently, a clinical relevance in children <1 year of age cannot be excluded, while preclinical data do not indicate a safety concern for children older than 1 year.