Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors.

Abstract Introduction In vivo profiles of aldosterone synthaseinhibitors (ASIs) have been investigated utilizing various rodent models. Due to lack of CYP17 activity, rodents produce corticosterone rather than cortisol as that of humans, which raised concern to their effectiveness in translational pharmacological characterization of ASI. Methods A rhesus monkey model that combines a low sodium dietwith adrenocorticotropin (ACTH) treatment was developed. Plasma concentrations of steroid metabolites associated with reactions catalyzed by CYP11B2 and CYP11B1 were measured concurrently by a UPLC/MS method. Results Plasma concentration of aldosteronein regular diet fed rhesus monkeys was low at 109 pg/mL. Aldosteroneconcentrations were increased to 252 pg/mL when animals were maintained on a low sodium dietfor 3 weeks, and to 300 pg/mL with ACTH treatment at 0.3 mg/kg. The combination of low sodium dietwith ACTH treatment further increased plasma concentration of aldosteroneto 730 pg/mL and other steroid metabolites at various levels. Intravenous administration of ASI, fadrozole(0.001–1 mg/kg) or LCI699 (0.003–3 mg/kg), led to dose-dependent reductions in aldosteroneand 18-hydroxycorticosterone, increases in 11-deoxycorticosteroneand 11-deoxycortisol, and bell-shaped changes in cortisol and corticosterone. In vivo selectivity of CYP11B2/CYP11B1 for fadrazole was 26-fold and LCI-699 was 27-fold, which was consistent with relative selectivity using in vitro values from recombinant cells transfected with rhesus monkey CYP11B2 and CYP11B1. Discussion This model enables concurrent characterization of pharmacokinetics, pharmacodynamics and selectivity of CYP11B2 over CYP11B1 inhibition in the same animal. It may be used as a translational model for pharmacological characterization of ASI.