istration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
12.3 Pharmacokinetics
Valsartan: Valsartan peak plasma concentration is 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 the capsule formulation is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Hydrochlorothiazide: Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours.
Geriatric: 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 [see Dosage and Administration(2.1)].
Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: 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 <10mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan [see Dosage and Administration(2.1)].
In a study of patients with impaired renal function (mean creatinine clearance of 19mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
Hepatic Insufficiency: 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. Care should be exercised in patients with liver disease [see Dosage and Administration(2.1)].
Distribution
Valsartan: The steady state volume of distribution of valsartan after intravenous administration is small (17L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Metabolism
Valsartan: 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.
Hydrochlorothiazide: Is not metabolized.
Excretion
Valsartan: Valsartan, when administered as an ora |
