Relevance of clinical pharmacological models for the evaluation of therapeutic dose range of an AT1-receptor antagonist.
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.
Brunner
H R
HR
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. laeis@sankyo-europe.de
Nussberger
J
J
D000328:Adult; D000803:Angiotensin I / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D015337:Multicenter Studies as Topic; D000068557:Olmesartan Medoxomil; D016032:Randomized Controlled Trials as Topic; D044140:Receptor, Angiotensin, Type 1; D012720:Severity of Illness Index; D013777:Tetrazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; D000803:Angiotensin I