Pharmacokinetics of Multiple Doses of Valsartan in Patients With Heart Failure

Angiotensin II has adverse actions in heart failure including vasoconstriction, aldosterone secretion, and activation of the sympathetic nervous system. Valsartan, a potent specific angiotensin II type 1 receptor blocker, may produce beneficial effects in heart failure. The purpose of this study was to evaluate the steady-state pharmacokinetics of valsartan 40, 80, and 160 mg each given every 12 h for 7 days in heart failure patients. Eighteen patients with chronic stable heart failure and left ventricular ejection fractions ≤ 40% received each dosing regimen starting with the 40-mg dose. On day 7 of each dosing period, serial blood samples were obtained over 12 h for pharmacokinetic assessment. Results showed that the mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased in a linear and nearly proportional manner with valsartan dose. A dose-proportionality assessment, based on a statistical power model, showed that doubling the dose increased the AUC and Cmax 1.8 times. The pharmacokinetics of valsartan are predictable in heart failure patients within the dose range of 40–160 mg BID. Age did not appear to have influenced the valsartan clearance in heart failure patients. The pharmacokinetic values were higher in heart failure patients than in healthy volunteers. All doses were generally safe and well tolerated.