Angiotensin II antagonist.
Pharmacology: Pharmacodynamics: The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from angiotensin I through angiotensin-converting enzyme (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 Ang 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, Ang 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 less (p<0.05) in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% vs 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% 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.
Administration of Tareg 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 hrs, and the peak reduction of blood pressure is achieved within 4-6 hrs. The antihypertensive effect persists over 24 hrs 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 Tareg has not been associated with rebound hypertension or other adverse clinical events.
In multiple-dose studies in hypertensive patients, Tareg 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 1 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 norepinephrine (PNE) levels after 28 days of treatment. In the 2nd study, which included only patients untreated with ACE inhibitors for at least 6 months prior to enrollment, valsartan significantly improved PCWP, systemic vascular resistance (SVR), cardiac output (CO) and SBP after 28 days of treatment. In the long-term Valsartan Heart Failure Trial (Val-HeFT) study, plasma norepinephrine 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 5010 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 β-blockers (36%). The mean duration of follow-up was nearly 2 years. The mean daily dose of Tareg in Val-HeFT was 254 mg. The study had 2 primary endpoints: All-cause mortality (time to death) and heart failure morbidity (time to 1st morbid event) defined as death, sudden death with resuscitation, hospitalization for heart failure, or administration of IV inotropic or vasodilator drugs for ≥4 hrs 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 1st heart failure hospitalization. The benefits were greatest in patients not receiving either an ACE inhibitor or a β-blocker. However, risk ratios favoring placebo were observed for those patients treated with the triple combination of a β-blocker, an ACE inhibitor and an ARB (angiotensin II receptor blocker), valsartan. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
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 2 times greater for the valsartan groups compared to the placebo group. The effects of valsartan compared to enalapril on exercise capacity using the 6-min 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 80-160 mg once daily was at least as effective as enalapril 5-10 mg twice daily, with respect to exercise capacity, as measured by the 6-min 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 dyspnea, fatigue, oedema 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.
Pharmacokinetics: Absorption of valsartan after oral administration is rapid, although the amount absorbed varies widely. Mean absolute bioavailability for Tareg is 23%. Valsartan shows multiexponential decay kinetics (t½α <1 hr and t½β about 9 hrs).
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.
Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady-state volume of distribution is low (about 17 L). Plasma clearance is relatively slow (about 2 L/hr) when compared with hepatic blood flow (about 30 L/hr). Of the absorbed dose of valsartan, 70% is excreted in the faeces and 30% in the urine, mainly as unchanged compound.
When Tareg is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hrs postdosing, plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect, and Tareg can therefore, be given either with or without food.
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 Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40-160 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/hr. Age does not affect the apparent clearance in heart failure patients.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in 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 nonbiliary origin and without cholestasis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction (see Precautions).