AN INTERACTION STUDY WITH CIMETIDINE AND THE NEW ANGIOTENSIN-II ANTAGONIST VALSARTAN

Objective: This was a randomised, open, three-way crossover study in 1 2 healthy male volunteers to determine the effect of a single oral dos e of cimetidine on the pharmacokinetics of a single oral dose of the a ngiotensin II receptor antagonist valsartan - and vice versa. The volu nteers received either valsartan alone (160 mg), or cimetidine alone ( 800 mg), or valsartan 1 h after cimetidine. The study was designed pri marily to detect a possible influence of cimetidine on the rate and ex tent of absorption of valsartan. Methods: Plasma concentrations of val sartan and cimetidine, measured by means of high-performance liquid ch romatography, were used to calculate pharmacokinetic parameters. The r ate of absorption of valsartan and the fraction of the dose absorbed a nd systemically available after oral administration were calculated us ing data from an i.v. study with valsartan in healthy young volunteers . Results: The pharmacokinetics of cimetidine - area under curve (AUC( 0-48) h), maximum concentration (C-max), time to reach C-max (t(max)) and apparent terminal plasma half-life (t(1/2)) - was not changed by c o-administration of valsartan. For valsartan, the AUC(0-48) h increase d by 7% and the C-max by 51% (ratio of geometric means) with coadminis tration of cimetidine. The higher value for C-max was attributed to th e initial increase in the rate of absorption of valsartan: k(a) was in creased 2.7-fold and another indicator for the rate of absorption, C-m ax/t(max), 2.2-fold. This effect was ascribed to inhibition of acid se cretion by cimetidine, which leads to a higher gastric pH, thereby inc reasing the solubility of valsartan; the t(1/2) of valsartan was not c hanged. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of th e possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inh ibit formation of the inactive metabolite of valsartan. Cimetidine-rel ated changes in the rate of elimination of valsartan were not anticipa ted, since the clearance from plasma occurs mainly by biliary excretio n of unchanged valsartan; metabolism and renal excretion are only mino r contributors. Therefore, even in the clinically relevant situation w ith multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in C-max, are n ot to be expected. This increase in C-max appears to be of no clinical significance. Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects.