College of Pharmacy, Chungnam National University, Daejeon, South Korea.
Faculty of Pharmacy, Haiphong University of Medicine and Pharmacy, Haiphong, Vietnam.
Eur J Drug Metab Pharmacokinet. 2024 Nov;49(6):701-714. doi: 10.1007/s13318-024-00917-0. Epub 2024 Sep 23.
Finerenone, a novel selective non-steroidal mineralocorticoid receptor antagonist, has been indicated in chronic kidney disease associated with type 2 diabetes mellitus. Considering the potential complications of diabetes, finerenone can be co-administered with various drugs, including fluconazole, diltiazem, and ritonavir. Given that finerenone is a substrate of cytochrome P450 (CYP) 3A4, the concurrent administration of finerenone with CYP3A4 inhibitors (diltiazem or fluconazole or ritonavir) could potentially lead to drug interactions, which may cause adverse events such as hyperkalemia. No studies have investigated interactions between finerenone and diltiazem or fluconazole or ritonavir. Therefore, this study aims to investigate the pharmacokinetic interaction of finerenone with diltiazem or fluconazole or ritonavir and to evaluate the impact of fluconazole on the pharmacodynamics of finerenone.
The pharmacokinetic study included four rat groups (n = 8 rats/group), including a control group (finerenone alone) and test groups (finerenone pretreated with diltiazem or fluconazole or ritonavir) using both non-compartment analysis (NCA) and population pharmacokinetic (pop-PK) modeling. The pop-PK model was developed using non-linear mixed-effects modeling in NONMEM (version 7.5.0). In the pharmacodynamic study, serum potassium (K) levels were measured to assess the effects of fluconazole on finerenone-induced hyperkalemia.
The NCA results indicated that the area under the plasma concentration-time curve (AUC) of finerenone increased by 1.86- and 1.95-fold when coadministered with fluconazole and ritonavir, respectively. In contrast, diltiazem did not affect the pharmacokinetics of finerenone. The pharmacokinetic profiles of finerenone were best described by a one-compartment disposition with first-order elimination and dual first-order absorption kinetics. The pop-PK modeling results demonstrated that the apparent clearance of finerenone decreased by 50.3% and 49.2% owing to the effects of fluconazole and ritonavir, respectively. Additionally, the slow absorption rate, which represents the absorption in the distal intestinal tract of finerenone, increased by 55.7% due to the effect of ritonavir. Simultaneously, a pharmacodynamic study revealed that finerenone in the presence of fluconazole caused a significant increase in K levels compared with finerenone alone.
Coadministration of finerenone with fluconazole or ritonavir increased finerenone exposure in rats. Additionally, the administration of finerenone in the presence of fluconazole resulted in elevated K levels in rats. Further clinical studies are required to validate these findings.
新型选择性非甾体盐皮质激素受体拮抗剂非奈利酮已被应用于 2 型糖尿病相关的慢性肾脏病。考虑到糖尿病的潜在并发症，非奈利酮可与多种药物联合使用，包括氟康唑、地尔硫卓和利托那韦。由于非奈利酮是细胞色素 P450（CYP）3A4 的底物，非奈利酮与 CYP3A4 抑制剂（地尔硫卓、氟康唑或利托那韦）同时给药可能会导致药物相互作用，从而导致高钾血症等不良反应。目前尚无研究探讨非奈利酮与地尔硫卓、氟康唑或利托那韦之间的相互作用。因此，本研究旨在探讨非奈利酮与地尔硫卓、氟康唑或利托那韦的药代动力学相互作用，并评估氟康唑对非奈利酮药效学的影响。
本药代动力学研究包括 4 组大鼠（每组 n=8 只大鼠），包括对照组（单独给予非奈利酮）和实验组（非奈利酮预先给予地尔硫卓、氟康唑或利托那韦），同时采用非房室分析（NCA）和群体药代动力学（pop-PK）建模。pop-PK 模型采用 NONMEM（版本 7.5.0）中的非线性混合效应建模进行开发。在药效学研究中，测量血清钾（K）水平以评估氟康唑对非奈利酮引起的高钾血症的影响。
NCA 结果表明，氟康唑和利托那韦分别使非奈利酮的血浆浓度-时间曲线下面积（AUC）增加 1.86 倍和 1.95 倍。相比之下，地尔硫卓对非奈利酮的药代动力学没有影响。非奈利酮的药代动力学特征最好通过一室模型描述，具有一级消除和双一级吸收动力学。pop-PK 建模结果表明，由于氟康唑和利托那韦的作用，非奈利酮的表观清除率分别降低了 50.3%和 49.2%。此外，由于利托那韦的作用，代表非奈利酮在远端肠道吸收的缓慢吸收速率增加了 55.7%。同时，药效学研究表明，与单独给予非奈利酮相比，氟康唑存在时非奈利酮导致 K 水平显著升高。
在大鼠中，非奈利酮与氟康唑或利托那韦联合给药会增加非奈利酮的暴露量。此外，在大鼠中给予非奈利酮时，氟康唑会导致 K 水平升高。需要进一步的临床研究来验证这些发现。
