Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system.
OBJECTIVE
The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose-response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated.


METHODS
The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose-response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose.


RESULTS
Angiotensin challenges exhibited a clear dose-response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24+/-6/20+/-5 mmHg for a unit dose of 1 microgram of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 microgram for systolic and 0.84 microgram for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities.


CONCLUSIONS
This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.
Buchwalder-Csajka
C
C
Division of Clinical Pharmacology, CHUV, Lausanne, Switzerland.
Buclin
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T
Brunner
H R
HR
Biollaz
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J
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000809:Angiotensins / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination / Q000379:methods; D017321:Clinical Trials, Phase I as Topic; D003625:Data Collection; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation / Q000379:methods; D006801:Humans; D008954:Models, Biological; D012044:Regression Analysis; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D000959:Antihypertensive Agents; D000804:Angiotensin II