Parkinson Joanna, Åstrand Magnus, Melin Johanna, Ericsson Hans
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50, Gothenburg, Sweden.
Clin Pharmacokinet. 2025 Sep 18. doi: 10.1007/s40262-025-01572-7.
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.
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).
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]). 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 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 m had a 1.44-fold (95% CI 1.22-1.69) increase in balcinrenone AUC compared with participants with an eGFR of 60 mL/min/1.73 m. 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.
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) in the intended patient population was less than 50% relative to a reference participant.
巴氯肾酮是一种新型盐皮质激素受体调节剂，根据临床前数据，它在不增加高钾血症风险的情况下维持心肾益处。巴氯肾酮与达格列净联合开发，用于治疗肾功能受损的心力衰竭（HF）和慢性肾脏病（CKD）。本研究的目的是应用群体药代动力学（popPK）方法描述巴氯肾酮的药代动力学（PK），并量化内在和外在因素对巴氯肾酮PK的影响。
评估基于六项临床研究的数据，这些研究的受试者包括健康参与者（NCT03843060、NCT03804645和NCT04798222）、肾功能受损参与者（NCT04469907）以及HF和CKD参与者（NCT03682497和NCT04595370），使用速释胶囊制剂（为3期研究所选）。
食物状态（即进食或未进食时服用巴氯肾酮）、肾功能（估计肾小球滤过率[eGFR]，采用eGFR对表观清除率的幂函数纳入模型）和研究类型（主要为健康参与者的1期研究或HF和CKD患者的1b/2b期研究）被确定为影响巴氯肾酮暴露量（稳态曲线下面积[AUC]）的协变量。食物状态对巴氯肾酮暴露量的影响较小，与空腹状态相比，进食时服用巴氯肾酮的AUC增加1.13倍（95%置信区间[CI]1.06 - 1.21）。观察到eGFR较低的参与者暴露量较高：eGFR为25 mL/min/1.73 m²的参与者与eGFR为60 mL/min/1.73 m²的参与者相比，巴氯肾酮AUC增加1.44倍（95%CI 1.22 - 1.69）。估计1期研究的参与者与1b/2b期研究的患者相比，暴露量低0.49倍（95%CI 0.41 - 0.60）。
在调整eGFR差异后，观察到HF和CKD参与者的表观清除率比健康参与者和肾功能受损者低约50%。这可能表明除肾功能外的其他因素可能影响巴氯肾酮的表观清除率。相对于参考参与者，协变量对目标患者群体中巴氯肾酮暴露量（AUC）的影响小于50%。
