title: The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study.
abstract: Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.
authors.affiliation: Encode Clinic, Reykjavik, Iceland. andersen@landspitali.is
authors.forename: Karl
authors.initials: K
authors.lastname: Andersen
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartman
authors.forename: Thomas
authors.initials: T
authors.lastname: Peppard
authors.forename: David
authors.initials: D
authors.lastname: Hermann
authors.forename: Peter
authors.initials: P
authors.lastname: Van Ess
authors.forename: Martin
authors.initials: M
authors.lastname: Lefkowitz
authors.forename: Angelo
authors.initials: A
authors.lastname: Trapani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood*; D062186:Arterial Pressure; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D055815:Young Adult
chemical_list: D007093:Imidazoles; D011725:Pyridines; D000450:Aldosterone; C553306:Osilodrostat; D019405:Cytochrome P-450 CYP11B2; D006854:Hydrocortisone