Background and objectives: In vitro and in vivo studies were performed with the novel, selective, nonsteroidal mineralocorticoid receptor antagonist finerenone to assess the relevance of inhibitory effects on the transporters breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3. These transporters are involved in the disposition of a number of drugs, including statins. Statins are also a frequent comedication in patients receiving finerenone. Therefore, inhibitory effects on BCRP and OATPs are of potential clinical relevance.
Methods: The effect on the transport of specific substrates of BCRP and OATP1B1/1B3 was assessed in cell-based in vitro assays with finerenone or its metabolites. A fixed-sequence crossover study in 14 healthy male volunteers investigated the effects of finerenone (40 mg once daily) on the pharmacokinetics of the index substrate rosuvastatin (5 mg) administered alone, simultaneously with, or approximately 4 h before finerenone. The effect of finerenone on the endogenous OATP substrates coproporphyrin I and III was also assessed.
Results: Based on in vitro findings and threshold values proposed in regulatory guidelines, finerenone appeared to be a potentially relevant inhibitor of all three transporters. Relevant inhibition could also not be ruled out for the finerenone metabolites M1a (OATP1B1) and M3a (OATP1B1 and OAT1B3), which prompted an investigation into the relevance of these findings in vivo. After administration on a background of finerenone 40 mg, all point estimates of area under the curve ratios (114.47% [rosuvastatin], 99.62% [coproporphyrin I; simultaneous], and 105.28% [rosuvastatin; 4 h separation]) and maximum concentration ratios (111.24% [rosuvastatin], 101.22% [coproporphyrin I], 89.14% [coproporphyrin III; simultaneous], and 96.84% [rosuvastatin; 4 h separation]) of the investigated substrates were within 80.0-125%. In addition, the 90% confidence intervals of the ratios were within the conventional no-effect boundaries of 80.0% and 125% for rosuvastatin after temporally separated administration, and for coproporphyrin I and III.
Conclusion: Administration of finerenone 40 mg once daily confers no risk of clinically relevant drug-drug interactions with substrates of BCRP, OATP1B1, or OATP1B3. The potential for relevant inhibition of these transporters suggested by in vitro findings was not confirmed in vivo.
Finerenone is a drug that is used to reduce the risk of adverse kidney and cardiovascular outcomes in patients with chronic kidney disease associated with type 2 diabetes mellitus. Taking more than one medicine, and often several at the same time, is common in these patients; therefore, it is important to investigate the drug–drug interaction potential of finerenone. These studies were carried out to assess the interaction potential of finerenone and its metabolites in both laboratory experiments and healthy volunteers. Initial laboratory experiments indicated that finerenone and its metabolites could inhibit transporters used by other drugs. A study in healthy volunteers was performed and demonstrated that finerenone is not associated with any clinically meaningful changes to drugs that are substrates for the transporters. The study in healthy volunteers demonstrates that medications that are substrates of these transporters can be safely co-administered with finerenone.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.