Population Pharmacokinetic Analysis of Balcinrenone in Healthy Participants and Participants with Heart Failure and Chronic Kidney Disease.

Background and objective: Balcinrenone is a novel mineralocorticoid receptor modulator which, based on preclinical data, maintains cardio-renal benefits without increasing hyperkalemia risk. Balcinrenone is developed in combination with dapagliflozin for the treatment of heart failure (HF) with impaired kidney function and chronic kidney disease (CKD). The aim of this work was to apply a population pharmacokinetic (popPK) approach to describe the pharmacokinetics (PK) of balcinrenone, and to quantify the effects of intrinsic and extrinsic factors on balcinrenone PK.

Methods: The assessment was based on data from six clinical studies in healthy participants (NCT03843060, NCT03804645, and NCT04798222), participants with renal impairment (NCT04469907), and participants with HF and CKD (NCT03682497 and NCT04595370) using the immediate-release capsule formulation (chosen for phase 3 studies).

Results: Food state (i.e., taking balcinrenone with or without food), renal function (estimated glomerular filtration rate [eGFR], incorporated using power function of eGFR on apparent clearance), and study type (phase 1 studies with mainly healthy participants or phase 1b/2b studies in patients with HF and CKD) were identified as covariates on balcinrenone exposure (area under the curve at steady-state [AUC_ss]). The magnitude of the impact of food state on balcinrenone exposure was minor, with a 1.13-fold (95% confidence interval [CI] 1.06-1.21) increase in AUC_ss when balcinrenone was taken with food compared with in a fasted state. Participants with a lower eGFR were observed to have higher exposure: those with an eGFR of 25 mL/min/1.73 m² had a 1.44-fold (95% CI 1.22-1.69) increase in balcinrenone AUC_ss compared with participants with an eGFR of 60 mL/min/1.73 m². Participants from phase 1 studies were estimated to have a 0.49-fold (95% CI 0.41-0.60) lower exposure compared with patients from phase 1b/2b studies.

Conclusions: Participants with HF and CKD were observed to have approximately 50% lower apparent clearance compared with healthy participants and those with renal impairment, after adjusting for differences in eGFR. This may indicate that factors other than renal function may impact the apparent clearance of balcinrenone. The impact of the covariates on balcinrenone exposure (AUC_ss) in the intended patient population was less than 50% relative to a reference participant.