Results from Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Effect of Finerenone on the Pharmacokinetics of Comedications.

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Citation

Heinig R, Gerisch M, Bairlein M, Nagelschmitz J, Loewen S

Results from Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Effect of Finerenone on the Pharmacokinetics of Comedications.

Eur J Drug Metab Pharmacokinet. 2020 Aug;45(4):433-444. doi: 10.1007/s13318-020-00610-y.

PubMed ID
32125665 [ View in PubMed
]
Abstract

BACKGROUND AND OBJECTIVES: In vivo studies were performed with the novel, selective, non-steroidal mineralocorticoid receptor antagonist finerenone to assess the relevance of inductive and/or inhibitory effects on cytochrome P450 (CYP) enzymes observed in vitro. METHODS: CYP isoenzyme-specific substrates were incubated in vitro with finerenone or its metabolites to investigate reversible and irreversible inhibitory as well as inductive potential. Three crossover studies in healthy male volunteers investigated the effects of finerenone (20 mg orally) on the pharmacokinetics of the index substrates midazolam (CYP3A4, n = 30), repaglinide (CYP2C8, n = 28) and warfarin (CYP2C9, n = 24). RESULTS: Finerenone caused direct inhibitory effects on CYP activities in vitro in the rank order CYP2C8, CYP1A1 > CYP3A4 > CYP2C9 and CYP2C19, but not on other major CYP isoforms. Moreover, irreversible inhibition of CYP3A4 was observed. The major metabolites of finerenone demonstrated minor reversible inhibition of CYP1A1, CYP2C9 and CYP3A4 with no hint of time-dependent inhibition of any CYP isoform. Calculations from in vitro data according to regulatory guidelines suggested likely inhibition of CYP2C8 and CYP3A4 in vivo, whereas this was not the case for CYP1A1, CYP2C9 and CYP2C19. Furthermore, finerenone and three of its metabolites were inducers of CYP3A4 in vitro with predicted weak-to-moderate in vivo relevance. Studies in healthy volunteers, prompted by these results, demonstrated no effect of finerenone on CYP isoenzymes for which in vitro data had indicated potential inhibition or induction. CONCLUSION: Administration of finerenone 20 mg once daily confers no risk of clinically relevant drug-drug interactions with substrates of cytochrome P450 enzymes.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
FinerenoneCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
FinerenoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details