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Single dose pharmacokinetics (PK) and pharmacodynamics (PD) of BR‐A‐657, an angiotensin II (AII) antagonist
Author(s) -
Lane A.,
Engmann E.,
Bryson S.,
Lee J.,
Tan H.,
Chi Y.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.114
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , antagonist , chemistry , aldosterone , plasma renin activity , enterohepatic circulation , angiotensin ii , excretion , medicine , endocrinology , renin–angiotensin system , receptor , metabolism , blood pressure
Background/Aims BR‐A‐657 is a nonpeptide AII receptor antagonist being developed for hypertension. This Phase I study investigated the safety, PK and PD of single doses of BR‐A‐657. Methods Fasted single oral tablet doses of 20–480 mg BR‐A‐657/placebo were administered to 40 healthy male subjects in a double‐blind, sequential group design. Results/Conclusions BR‐A‐657 was safe, well tolerated, and induced increases in plasma renin activity, angotensin I and AII that were not dose‐dependent. Maximal increases occurred between 6–8 h post‐dose, lasting up to 48h. There were no drug‐related changes in ACE or aldosterone. BR‐A‐657 was absorbed rapidly for all dose levels and demonstrated multiphasic disposition. For most subjects there were two peaks in the plasma concentration‐time profile, suggesting enterohepatic cycling. Half‐life could only be estimated for the higher dose levels (approx 9–16 h). Systemic exposure to BR‐A‐657 was broadly dose‐proportional. There were no marked differences in systemic exposure or disposition of BR‐A‐657 following adminstration of 240 mg in the fed state. Urinary excretion of BR‐A‐657 was low, suggesting non‐renal elimination. Clinical Pharmacology & Therapeutics (2005) 77 , P59–P59; doi: 10.1016/j.clpt.2004.12.114