osilodrostat and Hyperaldosteronism

We describe the clinical investigation of the first generation aldosterone synthase inhibitor, LCI699, in patients with essential, uncontrolled, resistant, or secondary hypertension. LCI699 competitively reduced blood pressure at lower doses yet counterintuitive effects were observed at higher doses.. An extensive endocrine biomarker analysis was performed to better understand the pharmacological mechanism of the drug.. The interference of LCI699 in the renin-angiotensin-aldosterone system occurred with limited target selectivity, as a dose-dependent compensatory stimulation of the hypothalamic-pituitary-adrenal feedback axis was discovered. Thus, LCI699 affected two endocrine feedback loops that converged at a single point, inhibiting the 11β-hydroxylase reaction in the adrenal gland, leading to supraphysiological levels of 11-deoxycortiscosterone. The accumulation of this potent mineralocorticoid may explain the blunted blood pressure response to LCI699.. Future aldosterone synthase inhibitors may improve their target selectivity by sparing the 11β-hydroxylase reaction and preferentially inhibiting one of the two other enzymatic reactions mediated by aldosterone synthase.

Topics: Adolescent; Adrenal Glands; Adult; Aged; Aldosterone; Antihypertensive Agents; Biomarkers; Blood Pressure; Cytochrome P-450 CYP11B2; Desoxycorticosterone; Double-Blind Method; Essential Hypertension; Female; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Hypothalamus; Imidazoles; Male; Middle Aged; Prospective Studies; Pyridines; Renin-Angiotensin System; Steroid 11-beta-Hydroxylase; Treatment Outcome; Young Adult

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.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Aldosterone; Blood Pressure; Cytochrome P-450 CYP11B2; Female; Humans; Hydrocortisone; Hyperaldosteronism; Imidazoles; Intention to Treat Analysis; Male; Middle Aged; Potassium; Pyridines; Renin

[Figure: see text].

Topics: Cytochrome P-450 CYP11B2; Drug Design; Humans; Hyperaldosteronism; Hypertension; Imidazoles; Molecular Structure; Pyridines