Insights Into Aldosterone Regulation Through Pharmacokinetic–Pharmacodynamic Modeling of an Aldosterone Synthase Inhibitor

Aldosterone is a mineralocorticoid hormone essential for regulating renal function and blood pressure. Despite its clinical relevance, key aspects of aldosterone pharmacokinetics (PK) and physiological dynamics remain incompletely understood. In serial stages, we developed a semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to characterize aldosterone dynamics under conditions of circadian production and inhibition by lorundrostat, a selective aldosterone synthase inhibitor. Lorundrostat PK from published single- and multiple-dose studies in healthy subjects was modeled using a linear hybrid two-compartment model (2CM) with food-dependent absorption and adrenal distribution. Separate assessment of aldosterone PK yielded 2CM properties that were used in defining both the circadian production and adrenal suppression by lorundrostat. Aldosterone concentrations from 24-hour pre-dose phases were characterized with dual harmonic circadian functions with fasting-induced shifts in the timing and amplitude of hormone production. Lorundrostat suppression of aldosterone production was fitted with an extended indirect response model utilizing both the circadian production and 2CM aldosterone PK. Synthesis inhibition was about 90% while IC₅₀ values were attained at low doses. Such inhibition induced gradual compensatory increases in plasma renin activity, with rebound effects on aldosterone expected after 7 days of dosing and later. Sensitivity analysis supported the determinants of aldosterone dynamics in the model. This model provides a systems-level framework to disentangle physiological and pharmacological drivers of aldosterone regulation, supports trial design for aldosterone synthase inhibitors, and may inform the development of more complex models for RAAS control of renal and cardiovascular function.