Pharmacokinetic and Pharmacodynamic Interaction of Finerenone with Diltiazem, Fluconazole, and Ritonavir in Rats.

Autor: Bui TT; College of Pharmacy, Chungnam National University, Daejeon, South Korea.; Faculty of Pharmacy, Haiphong University of Medicine and Pharmacy, Haiphong, Vietnam., Kim SH; College of Pharmacy, Chungnam National University, Daejeon, South Korea., Jung W; College of Pharmacy, Chungnam National University, Daejeon, South Korea.; Senior Health Convergence Research Center, Chungnam National University, Daejeon, South Korea., Yang SY; College of Pharmacy, Chungnam National University, Daejeon, South Korea., Tran QT; Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi, 12116, Vietnam.; PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, No.167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi, 11313, Vietnam., Lee H; Department of Bio-AI Convergence, Chungnam National University, Daejeon, South Korea., Park S; College of Pharmacy, Chungnam National University, Daejeon, South Korea., Ngo LT; College of Pharmacy, Chungnam National University, Daejeon, South Korea. lien.ngothi@phenikaa-uni.edu.vn.; Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi, 12116, Vietnam. lien.ngothi@phenikaa-uni.edu.vn.; PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, No.167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi, 11313, Vietnam. lien.ngothi@phenikaa-uni.edu.vn., Yun HY; College of Pharmacy, Chungnam National University, Daejeon, South Korea. hyyun@cnu.ac.kr.; Department of Bio-AI Convergence, Chungnam National University, Daejeon, South Korea. hyyun@cnu.ac.kr.; Senior Health Convergence Research Center, Chungnam National University, Daejeon, South Korea. hyyun@cnu.ac.kr., Chae JW; College of Pharmacy, Chungnam National University, Daejeon, South Korea. jwchae@cnu.ac.kr.; Department of Bio-AI Convergence, Chungnam National University, Daejeon, South Korea. jwchae@cnu.ac.kr.; Senior Health Convergence Research Center, Chungnam National University, Daejeon, South Korea. jwchae@cnu.ac.kr.
Jazyk: angličtina
Zdroj: European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2024 Nov; Vol. 49 (6), pp. 701-714. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1007/s13318-024-00917-0
Abstrakt: Background and Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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