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Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects

  • Pharmacodynamics
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Abstract

Valsartan (CGP 48933), a specific blocker of the angiotensin II (Ang II) receptor subtype 1 (AT1 receptor) was administered in single, oral doses of 40 mg and 80 mg to six healthy, normotensive male volunteers in a double-blind, placebo-controlled, randomized crossover trial. The aims of the study were a) to assess the extent, time course and dose-dependency of inhibition of the pressor effect of exogenous Ang II; and b) to attempt to correlate AT1 receptor blockade with the drug levels in plasma and with other markers of biological activity of the trial drug such as plasma renin activity (PRA).

Using the Finapres device and i.v. bolus injections of exogenous Ang II, AT1 receptor blockade was assessed by measuring blood pressure (BP) and heart rate (HR) on a beat-by-beat basis. A dose-response curve for Ang II was obtained for each subject before and at 2,4, 6,8 and 24h after administration of placebo and of the two doses of valsartan. PRA was measured with a conventional radioimmunoassay method.

Data evaluation included a) descriptive analysis of the changes of the Ang II dose-response curves after valsartan, as compared to the curve on placebo; b) calculation of the pressor dose D30 of Ang II at each timepoint, using linear regression; c) assessment of the effect of 4 μg Ang II on systolic BP and HR and the calculation of the percentage inhibition of these effects after valsartan; d) description of the relationship between drug levels in plasma and the measures of AT1 blockade, including pharmacokinetic-pharmacodynamic modeling with an Emax model for the percentage inhibition of systolic BP and HR.

It is concluded that (a) the methodology used is suitable to evaluate AT1 receptor blockade in man; (b) instead of using a full dose-response curve for Ang II at each timepoint, an abbreviated approach with only one pre-determined Ang II dose may be adopted without substantial loss of information; (c) valsartan is an inhibitor of the AT1 receptor in man, with a mean Emax of 74% and a mean IC50 of 0.53 μmol·1−1 for the blood pressure response to exogenous Ang II; (d) receptor blockade after single oral doses of 40 mg and 80 mg valsartan reaches its maximum at 2 h and is detectable up to 24 h after administration; (e) despite a doubling of systemic exposure, the relationship between dose and receptor blockade appears to be rather flat in the dose range 40 to 80 mg; and (f) valsartan is well tolerated by healthy subjects in the dose range tested.

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Authors and Affiliations

  1. Research and Development Departments, Pharma Division, Ciba-Geigy Limited, CH-4002, Basel, Switzerland

    P. Müller, T. Cohen, M. de Gasparo, A. Sioufi, A. Bacine-Poon & H. Howald

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  1. P. Müller
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  2. T. Cohen
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  3. M. de Gasparo
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Müller, P., Cohen, T., de Gasparo, M. et al. Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. Eur J Clin Pharmacol 47, 231–245 (1994). https://doi.org/10.1007/BF02570503

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  • DOI: https://doi.org/10.1007/BF02570503

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