Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator

British Journal of Clinical Pharmacology
Fredrik ErlandssonJudith Hartleib-Geschwindner

Abstract

AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977. A first-in-human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over four-period clinical trial was performed. Twenty-three 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. AZD9977 at doses from 5 to 1200 mg was 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 mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na+ K+ ]. 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 exog...Continue Reading

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Citations

Mar 1, 2019·Journal of the Renin-angiotensin-aldosterone System : JRAAS·Krister BambergJudith Hartleib-Geschwindner
Mar 3, 2020·Current Hypertension Reports·Daisuke SuetaKenichi Tsujita
Nov 13, 2020·Drug Development Research·Vishal PatelMukul Jain
Oct 27, 2021·British Journal of Pharmacology·Dorien ClarisseAchim Lother
Nov 24, 2021·British Journal of Pharmacology·Ulrich KintscherPeter Kolkhof

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