The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

Journal of Translational Medicine

Research

David W Piotrowski¹  Kristen Near¹  Rena J Eudy¹  Carine M Boustany-Kari²  Kevin Sweeney³  Vaishali Sahasrabudhe³  Amanda King-Ahmad⁴  Meera Tugnait⁴  Mary Ellen Banker⁵  Paula Loria⁵ 

[1] Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer, Eastern Point Road, Groton, CT, USA;Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer, Eastern Point Road, Groton, CT, USA;Boehringer Ingelheim, Ridgefield, CT, USA;Department of Clinical Pharmacology, Pfizer, Eastern Point Road, Groton, CT, USA;Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer, Eastern Point Road, Groton, CT, USA;Department of Pharmatherapeutics Research CoEs, Pfizer, Eastern Point Road, Groton, CT, USA;

关键词: Aldosterone;    Plasma Renin Activity;    Mineralocorticoid Receptor;    Eplerenone;    Plasma Aldosterone;   

DOI  :  10.1186/1479-5876-9-180

 received in 2011-06-23, accepted in 2011-10-21,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAccumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound.MethodsThe effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans.ResultsIn Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human.ConclusionsUrinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively.Trial RegistrationFor clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements.Clinical study reference A6141115: http://clinicaltrials.gov, http://NIHclinicaltrails.gov; NCTID: NCT00990223

【 授权许可】

Unknown   
© Eudy et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.