Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects

Aims: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects.

Methods: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed.

Results: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (C_max ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUC_last ) and AUC from zero until infinity (AUC_inf ) were 1.13 (1.05, 1.20) ng mL^-1 , 1.47 (1.40, 1.54) ng h mL^-1 and 1.53 (1.45, 1.62) ng h mL^-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone C_max , AUC_last and AUC_inf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively.

Conclusion: Itraconazole increased esaxerenone AUC_inf by 53.1%, and rifampicin decreased esaxerenone AUC_inf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.