Pharmacology: Pharmacodynamics: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin 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 angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular 1 smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin 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 20000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II 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 200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin 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 angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
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 reported.
Removal of the negative feedback of angiotensin II is reported is reported to cause 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 have been reported after administration of valsartan; with very little effect on serum potassium.
In reported multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, there was no clinically significant effects reported with valsartan on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
In reported multiple-dose studies in hypertensive patients, no notable effects were reported with valsartan on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Pharmacokinetics: Valsartan peak plasma concentration is reported to reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for valsartan is about 25% (range 10% to 35%). With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC max and Cmax values of valsartan increase approximately linearly with increasing dose over the max clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). 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 CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism. 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).
Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Special Populations: Pediatric: In a reported study of pediatric hypertensive patients (1 to 16 years of age) given single doses of a suspension of valsartan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was reported to be similar to that of adults receiving the same formulation.
Geriatric: Exposure (measured by AUC) to valsartan is reported to be higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary (see DOSAGE & ADMINISTRATION).
Gender: Pharmacokinetics of valsartan is not reported to differ significantly between males and females.
Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to that reported in healthy volunteers. AUC and Cmax values of max 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.
Renal Insufficiency: There is no reported correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. No studies have been reported in patients with severe impairment of renal function (creatinine clearance <10 ml/min). Valsartan is not removed from the plasma by hemodialysis. Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤30 ml/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 ml/min) or moderate (CrCl 30 to 60 ml/min) renal impairment. In the case of severe renal disease, exercise care with dosing of valsartan (see DOSAGE & ADMINISTRATION).
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease are reported to have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). Valsartan is contraindicated in patients with severe hepatic impairment; biliary cirrhosis and cholestasis (see CONTRAINDICATIONS). In patients with mild to moderate hepatic impairment without cholestasis, it should be used with caution and the dose of valsartan should not exceed 80 mg (see DOSAGE & ADMINISTRATION).
Toxicology: Preclinical Safety Data: Non-clinical data have not reported any special hazard for humans based on reported studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In reported non-clinical safety studies in rats, high doses of valsartan (200 to 600 mg/kg body weight) which are approximately 6 and 18 times the maximum recommended human dose, caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10 to 35% of the maximum recommended pediatric dose of 4 mg/kg/day on systemic exposure basis) reportedly produced persistent, irreversible kidney damage. These effects represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers and are reported in rats 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. 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 reported preclinical data does not indicate a safety concern for children older than 1 year.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of carcinogenicity reported when valsartan was administered to mice and rats for up to 2 years at doses up to 2.6 and 6 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).
Mutagenicity assays have not reported any valsartan-related effects at either the gene or chromosome level.
Valsartan had no reported adverse effects on the reproductive performance of male or female rats at oral doses up to 6 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).
No teratogenic effects have been reported when valsartan was administered to pregnant mice and rats at oral doses up to 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 have been reported 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 reported at doses of 5 and 10 mg/kg/day. The adverse effect reported at 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.