PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES OF AN ANGIOTENSIN-II RECEPTOR ANTAGONIST - CHARACTERIZATION BY USE OF SCHILD REGRESSION TECHNIQUE IN MAN

Objective: The pharmacodynamic properties of a new angiotensin II rece ptor antagonist (BAY 10-6734) in humans were to be quantitatively char acterized from the rightward shifts of the agonist dose-response curve s after administration of different doses of the antagonist, Methods: 24 healthy male volunteers received single oral doses of 20-300 mg BAY 10-6734, Before and up to 23 h post dosing (p.d.) plasma was obtained for HPLC measurement of parent compound and active metabolite BAY 10- 6735, Exogenous angiotensin II was infused in increasing dose steps un til blood pressure had increased by +25 mmHg, Angiotensin II dose-resp onse curves were fitted individually using the sigmoidal E-max model. From the antagonist-induced rightward shifts, as compared to a premedi cation curve, dose ratios (DR) were determined and DR-1 plotted versus applied dosages and measured plasma concentrations, From these Schild regression plots the fictive doses and concentration (K-i) inducing a DR-1 = 1, i.e. a 2-fold shift in agonist dose-response curves, were d erived. The ''doubling (t(2.0)) time'' of the apparent K-i doses was c alculated. Results: BAY 10-6734 dose-dependently induced rightward shi fts of the angiotensin II blood pressure response curves, mean maximum DR at 2 h p.d. ranged from 42 (80 mg) to 216 (300 mg), and at 23 h p. d. decreased to about 2 (80 mg) to 4 (300 mg), Pharmacodynamic (3.4-4. 6 h) and pharmacokinetic half-lives (3.4-4.3 h) were nearly identical. Apparent K-i doses increased from about 1-2 mg at 2 h p.d. to about 8 0-100 mg at 23 h p.d., their time course revealed a doubling (t(2.0)) time of 3.5-3.8 h. A K-i concentration of about 10 mu g/l was obtained for the active metabolite BAY 10-6735. Conclusions: Oral administrati on of BAY 10-6734 in man antagonized angiotensin II dose blood pressur e response curves in a dose-dependent manner. The time kinetics of the pharmacodynamic effect, derived from the decay of DR-1 values, as wel l as the-doubling time of the apparent K-i values well agreed with the pharmacokinetic half-life, Schild regression revealed competitive ang iotensin II antagonistic properties within the dose/concentration rang e tested. This technique was shown to be an adequate means to evaluate pharmacodynamic potency and kinetic behavior of an angiotensin II rec eptor antagonist in vivo.