Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD997, a novel, selective mineralocorticoid receptor modulator

Summary

Aims

AZD9977 is the first MR modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in pre-clinical studies. The aim was to perform the initial clinical assessment of AZD9977.

Methods

A first in man trial explored doses from 5-1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over 4 period clinical trial was performed. 23 healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis.

Results

AZD9977 at doses from 5-1200 mg were safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na⁺]/ [K⁺] as eplerenone when using fludrocortisone as MR agonist, and the combination had an additive effect on ln [Na⁺K⁺].

Conclusions

The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.

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