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

Abstract

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.

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

“…The aldosterone response to AZD9977 supports target engagement, and the lack of effect on electrolytes is consistent with its hypothesized mechanism of action. The study confirmed the safety profile and pharmacodynamic effects of AZD9977 observed in a previous single‐dose phase I study in healthy volunteers . The results of these studies suggest that AZD9977 may protect against aldosterone‐mediated organ damage, with a reduced risk of hyperkalemia compared with MR antagonists.…”

“…Additional support for this explanation is the similar dose proportionality in exposure on day 1 and day 8, the time needed to reach steady‐state, and the stable morning and evening C trough levels at steady‐state. Moreover, regional absorption of AZD9977 was explored in a previous study and the extent of colonic absorption was reported to be sufficient for development of a controlled release formulation . AZD9977 did not increase 4β‐hydroxycholesterol levels, indicating no induction of CYP450 3A4/3A5.…”

“…Doses were escalated to AZD9977 150 and 300 mg in the subsequent cohorts after review of safety and pharmacokinetic data from previous cohorts. The starting dose was based on preclinical pharmacokinetic–pharmacodynamic modeling data and on the previous observation that single doses of AZD9977 up to 1,200 mg were well‐tolerated in healthy men . AZD9977 was administered as a 15 mg/mL oral suspension in a volume of 240 mL.…”

“…25 In a first-in-human phase I study, single doses of AZD9977 covering the range 5-1,200 mg had a good safety profile and were well-tolerated in healthy volunteers. 26 AZD9977 was rapidly absorbed after oral administration, with dose-proportional systemic exposure up to 200 mg and a short plasma half-life (t 1/2 ) of 2-3 hours. The human plasma protein binding of AZD9977 is 82%, and in vitro metabolism studies have shown that the cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 are the main CYP isoforms involved in the metabolism of AZD9977.…”

“…The binding of AZD9977 to the MR induces a unique protein conformation in the MR that is distinct from the one induced by MR antagonists, and may modify the interaction pattern of the receptor with transcriptional co‐activators . In a first‐in‐human phase I study, single doses of AZD9977 covering the range 5–1,200 mg had a good safety profile and were well‐tolerated in healthy volunteers . AZD9977 was rapidly absorbed after oral administration, with dose‐proportional systemic exposure up to 200 mg and a short plasma half‐life (t 1/2 ) of 2–3 hours.…”