Kidney Week

Abstract: SA-PO1009

MR Modulator AZD9977 Causes Reduced Plasma Potassium Elevation Compared to Eplerenone After Potassium Challenge in CKD Model

Session Information

• Fluid and Electrolytes: Basic - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Bamberg, Krister, AstraZeneca, Molndal, Sweden

Krister Bamberg,

• William-Olsson, Lena, AstraZeneca, Molndal, Sweden

Lena William-Olsson,

• El moghrabi, Soumaya, INSERM U1138 - Centre de Recherche des Cordeliers, Paris, France

Soumaya El moghrabi,

• Jaisser, Frederic, INSERM U1138, Paris Cedex 13, France

Frederic Jaisser,

• Hartleib-Geschwindner, Judith, AstraZeneca, Molndal, Sweden

Judith Hartleib-Geschwindner,

Background

Hyperkalemia is a potential side effect of mineralocorticoid receptor (MR) antagonists since they cause renal Na⁺ excretion and K⁺ retention. MR antagonist dependent renal Na⁺ excretion can be studied acutely in rodents and translates well to man. However, rodents are largely refractory to plasma K⁺ elevations and hence the potential reduced liability of novel MR modulators to cause hyperkalemia is difficult to explore in rodent models.

Methods

Acute effects on 7 hours urine electrolyte excretion were studied after single dose administration of 30, 100 or 200 mg/kg eplerenone or AZD9977 to mice fed a low salt (0.02%) diet for 3 days prior to dosing. Effects on plasma K⁺ elevations were studied in 5/6 nephrectomised mice with developed chronic kidney disease (CKD) treated for 5 days with 100 mg/kg bid eplerenone or AZD9977 followed by a KCl load over night before measuring plasma K⁺.

Results

100 and 200 mg/kg eplerenone treatment caused an increased urinary Na⁺/K⁺ ratio (0.57±0.11, p=0.0022 and 0.68±0.08, p<0.0001, respectively) compared to vehicle (0.06±0.09). AZD9977 exposure did not alter urinary Na⁺/K⁺ ratio.
Subchronic treatment with eplerenone or AZD9977 in CKD at exposures 14x above in vitro IC₅₀ did not alter plasma K⁺ levels. Eplerenone vs vehicle treatment followed by K⁺ challenge led to a robust elevation of plasma K⁺ (6.5±0.2 vs 5.4±0.2 mM, p<0.001). The plasma K⁺ elevation after AZD9977 treatment and K+ challenge (5.9±0.2 mM, p=0.042 vs vehicle) was significantly lower compared to eplerenone (p=0.0045).

Conclusion

AZD9977 is a novel MR modulator developed to yield maximal efficacy on organ protection and minimal effects on plasma K⁺. AZD9977 did not cause the typical acute urinary Na⁺ excretion in mice observed with MR antagonists. Lack of effect on urinary electrolytes translated to a reduced plasma K⁺ elevation in a mouse CKD model after potassium challenge. Whether the reduced effect on plasma K⁺ observed with AZD9977 vs eplerenone will translate into a clinically meaningful differentiation will be explored in clinical studies.

Funding

• Commercial Support – AstraZeneca