Relevance of clinical pharmacological models for the evaluation of therapeutic dose range of an AT1-receptor antagonist

Details

Serval ID
serval:BIB_A739988072D4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Relevance of clinical pharmacological models for the evaluation of therapeutic dose range of an AT1-receptor antagonist
Journal
Journal of Hypertension. Supplement
Author(s)
Brunner  H. R., Nussberger  J.
ISSN
0952-1178 (Print)
Publication state
Published
Issued date
06/2001
Volume
19
Number
1
Pages
S15-20
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun
Abstract
Clinical pharmacological models Antihypertensive drugs affecting the renin-angiotensin system (RAS) can be evaluated in single-dose studies in healthy volunteers challenged with angiotensin I or II, or in subjects in whom the RAS has been activated by salt depletion. Such pharmacological studies can be used to investigate dose-response relationships. Objective The relevance of these models in predicting therapeutic dose range has been evaluated by comparing the results of pharmacological studies with those of a conventional dose-finding study in hypertensive patients with the new AT1-receptor antagonist olmesartan medoxomil. Results In healthy volunteers, 2.5-40 mg olmesartan medoxomil single doses significantly inhibited the pressor response to exogenous angiotensin I. A dose-response relationship was observed, with relevant (> 75%) inhibition occurring at doses of 10 mg and above. In a single-dose crossover study in patients with mild-to-moderate hypertension receiving a sodium-restricted diet, statistically significant lowering of mean 24-h blood pressure, measured by ambulatory blood pressure monitoring, was observed at doses of 10-80 mg. By comparison, a large-scale (n = 792), placebo-controlled, dose-ranging study in patients with mild-to-moderate hypertension likewise showed significant superiority over placebo for 10-80 mg olmesartan medoxomil once-daily doses. Conclusion Single-dose clinical pharmacology studies provided an accurate indication of the effective dose range of a new AT1-receptor antagonist Such models can be useful in identifying, for more detailed study, the likely therapeutic dose range of new drugs acting on the RAS. However, the dose-response still requires testing in large target populations.
Keywords
Adult Angiotensin I/pharmacology Antihypertensive Agents/*administration & dosage/pharmacology/therapeutic use Blood Pressure/*drug effects Blood Pressure Monitoring, Ambulatory Circadian Rhythm Cross-Over Studies Diet, Sodium-Restricted Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Humans Hypertension/drug therapy/physiopathology Imidazoles/*administration & dosage/pharmacology/therapeutic use Male Multicenter Studies Randomized Controlled Trials Receptor, Angiotensin, Type 1 Receptors, Angiotensin/*antagonists & inhibitors Severity of Illness Index Tetrazoles/*administration & dosage/pharmacology/therapeutic use
Pubmed
Create date
05/03/2008 16:39
Last modification date
20/08/2019 15:12
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