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Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty\u2010seven male participants aged 23\u201345\u00a0years were randomized 3:1 to receive oral AZD9977 or placebo for 8\u00a0days (with twice\u2010daily dosing on days 2\u20137), in dose cohorts of 50, 150, and 300\u00a0mg (AZD9977, <jats:italic>n<\/jats:italic>\u00a0=\u00a06 per cohort; placebo, <jats:italic>n<\/jats:italic>\u00a0=\u00a03 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50\u20130.84\u00a0hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half\u2010life increased with dose. Steady\u2010state was reached after 3\u20134\u00a0days, with dose\u2010dependent accumulation of 1.2\u20131.7\u2010fold. Renal clearance was 5.9\u20136.5\u00a0L\/hour and 24\u201337% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days \u22121 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well\u2010tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977.<\/jats:p>","DOI":"10.1111\/cts.12705","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T15:03:36Z","timestamp":1570201416000},"page":"275-283","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study"],"prefix":"10.1111","volume":"13","author":[{"given":"Andrew","family":"Whittaker","sequence":"first","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa M.","family":"Kragh","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, ADME and AI Clinical Pharmacology &amp; Safety Sciences BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Hartleib\u2010Geschwindner","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muna","family":"Albayaty","sequence":"additional","affiliation":[{"name":"Early Phase Clinical Unit PAREXEL Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Backlund","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Greasley","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Heijer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Biologics and Bioanalysis Clinical Pharmacology and Safety Sciences R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Kjaer","sequence":"additional","affiliation":[{"name":"Early Biometrics and Statistical Innovation, Data Science and AI BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Forte","sequence":"additional","affiliation":[{"name":"Early Phase Clinical Unit PAREXEL Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Unwin","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Wernevik","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Ericsson","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, ADME and AI Clinical Pharmacology &amp; 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