Results from Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Effect of Finerenone on the Pharmacokinetics of Comedications
| Autor: | Michaela Bairlein, Stephanie Loewen, Michael Gerisch, Roland Heinig, Johannes Nagelschmitz |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Finerenone Adolescent Midazolam Administration Oral Pharmacology 030226 pharmacology & pharmacy Models Biological Substrate Specificity Cytochrome P-450 CYP2C8 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacokinetics Double-Blind Method Piperidines In vivo Germany Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans heterocyclic compounds Pharmacology (medical) Drug Interactions Naphthyridines CYP2C8 CYP2C9 Cytochrome P-450 CYP2C9 Mineralocorticoid Receptor Antagonists Cytochrome P-450 Enzyme Inducers Cross-Over Studies CYP3A4 biology Chemistry Cytochrome P450 Middle Aged In vitro Isoenzymes 030220 oncology & carcinogenesis biology.protein Carbamates Warfarin |
| Zdroj: | European journal of drug metabolism and pharmacokinetics. 45(4) |
| ISSN: | 2107-0180 |
| Popis: | 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. 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). 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. Administration of finerenone 20 mg once daily confers no risk of clinically relevant drug–drug interactions with substrates of cytochrome P450 enzymes. |
| Databáze: | OpenAIRE |
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