Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism.
We report the first administration of an orally active aldosterone synthase inhibitor, LCI699, to 14 patients with primary aldosteronism. After a 2-week placebo run-in, patients received oral LCI699 (0.5 mg BID) for 2 weeks, LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in hormone concentrations, plasma potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of LCI699 (-68%; P<0.0001) and to 133 pmol/L (95% CI: 100 to 177 pmol/L) after 1.0 mg of LCI699 (-75%; P<0.0001). Plasma 11-deoxycorticosterone concentrations increased by 710% after 0.5 mg of LCI699 (P<0.0001) and by 1427% after 1.0 mg of LCI699 (P<0.0001). The plasma potassium concentration increased from 3.27±0.31 to 4.03±0.33 mmol/L (P<0.0001) after only 1 week on 0.5 mg of LCI699. Twenty-four-hour ambulatory systolic blood pressure decreased by -4.1 mm Hg (95% CI: -8.1 to -0.1 mm Hg) after 4 weeks of treatment (P=0.046). Basal plasma cortisol concentrations remained unchanged, whereas plasma adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of LCI699 (P=0.08) and by 113% after 1.0 mg of LCI699 (P<0.0001), and the plasma cortisol response to an adrenocorticotropic hormone test was blunted. All of the variables except plasma 11-deoxycorticosterone concentration returned to initial levels after the placebo. LCI699 was well tolerated. In conclusion, the administration of LCI699, up to 1.0 mg BID, effectively and safely inhibits aldosterone synthase in patients with primary aldosteronism. This 4-week treatment corrected the hypokalemia and mildly decreased blood pressure. The effects on the glucocorticoid axis were consistent with a latent inhibition of cortisol synthesis.
Amar
Laurence
L
Université Paris Descartes, Faculté de Médecine, Paris, France.
Azizi
Michel
M
Menard
Joël
J
Peyrard
Séverine
S
Watson
Catherine
C
Plouin
Pierre-François
PF
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood* / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006929:Hyperaldosteronism / Q000097:blood / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood*; D011725:Pyridines / Q000494:pharmacology*; D012083:Renin / Q000097:blood
D007093:Imidazoles; D011725:Pyridines; D000450:Aldosterone; C553306:Osilodrostat; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D011188:Potassium; D006854:Hydrocortisone