Muhammad Waqas Sadiq (1), Christine Ahlström (1), Ulrika Johansson (2), Krister Bamberg (2), Lena Williams-Olsson (2), Rasmus Jansson-Löfmark (1)
(1) CVMD iMed DMPK, AstraZeneca R&D, 431 83, Mölndal, Sweden, (2) CVMD iMed Bioscience, AstraZeneca R&D, 431 83, Mölndal, Sweden
Objectives: Mineralcorticoid receptor (MR) antagonism prevents the endogenous agonist aldosterone to retain sodium to be excreted in urine. The objective of this study was to build a quantitative understanding of this system after single doses to rats.
Methods: Various doses of aldosterone (MR agonist) and eplerenone (MR antagonist) were administered to rats in 12 different dosing combinations (n=75 rats). Animals were placed in metabolic chambers and urine was collected at serial time points for sodium excretion analysis (cumulative sodium excretion). In a separate group of animals the plasma concentrations of aldosterone and eplerenone were measured to quantify pharmacokinetic parameters. A population PK/PD model containing a pool-precursor model with competitive interaction was used to estimate the system parameters including rate and extent of tolerance, and the potencies of aldosterone and eplerenone.
Results: MR provocations displayed acute tolerance mechanisms that can be adequately described with the proposed population PK/PD model. The rate of tolerance (half-life) was estimated to approximately 4 hours. Eplerenone (MR antagonist) was estimated to be approximately 100-fold less potent than aldosterone (MR agonist). In the modelling process it was also evident that without appropriate study design, the potencies for the agonist and antagonist can easily correlate.
Conclusions: The competitive interaction mechanism for the mineralcorticoid receptor and the acute tolerance and rebound are key components that need to be considered when forward/back translating the potency of MR antagonists between species. These findings also highlights that when similar experimental setup to those described above are used in a clinical setting, the tolerance, feedback and competitive interaction need to be considered.
Reference: PAGE 25 (2016) Abstr 5996 [www.page-meeting.org/?abstract=5996]
Poster: Drug/Disease modeling - Endocrine