Multiple dose pharmacokinetics (PK) and pharmacodynamics (PD) of BR-A-657, an angiotensin II (AII) antagonist

Abstract

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 multiple doses of BR-A-657. Methods Fasted oral tablet doses of 120 & 360 mg BR-A-657/placebo were given once daily for 7 days to groups of 8 healthy male subjects in a double-blind, sequential group design. Results/Conclusions BR-A-657 was well tolerated following 120 mg but not 260 mg, with an increased incidence of low blood pressure and postural dizziness for the latter dose level. BR-A-657 induced increases in plasma renin activity and AII that were maximal 6–8 h post-dose and lasted up to 24h. These effects were dose-independent but the effect on AII was more pronounced on Day 7 than Day 1. There were no drug-related changes in ACE or aldosterone. On Days 1 & 7, BR-A-657 was rapidly absorbed and showed multiphasic disposition. Most subjects had two plasma concentration peaks, suggesting enterohepatic cycling. Steady-state was achieved for both dose levels following 3 doses, and there was slight accumulation on Day 7 (20–26%). Systemic exposure was broadly dose-proportional on Days 1 and 7, and urinary excretion was low on both days, suggesting non-renal elimination. Clinical Pharmacology & Therapeutics (2005) 77, P58–P58; doi: 10.1016/j.clpt.2004.12.113