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 (Cmax), area under the plasma concentration–time curve (AUC) from zero until the last measurable concentration (AUClast) and AUC from zero until infinity (AUCinf) 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 Cmax, AUClast and AUCinf 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 AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.

Background To investigate the effects of coadministration of esaxerenone with amlodipine on the pharmacokinetics (PK) of each drug, and of esaxerenone on the PK of digoxin. Methods In three open-label, single-sequence, crossover studies, healthy Japanese males received single oral doses of esaxerenone 2.5 mg (Days 1, 15), with amlodipine 10 mg/day (Days 8–18) (Study 1, N = 24); single doses of amlodipine 2.5 mg (Days 1, 21), with esaxerenone 5 mg/day (Days 8–25) (Study 2; N = 20); or digoxin 0.25 mg/day (Days 1–15) with esaxerenone 5 mg/day (Days 11–15) (Study 3; N = 20). PK parameters and safety were assessed. Results Study 1: esaxerenone peak plasma concentration (C max ) and time to C max were unaltered by amlodipine coadministration, but mean half-life was slightly prolonged from 18.5 to 20.9 h. Geometric least-squares mean (GLSM) ratios for C max , area under the plasma concentration–time curve (AUC) from zero to last measurable concentration and from zero to infinity for esaxerenone + amlodipine versus esaxerenone were 0.958, 1.154, and 1.173, respectively. Study 2: corresponding GLSM ratios for amlodipine + esaxerenone versus amlodipine were 1.099, 1.185, and 1.214. Study 3: esaxerenone did not markedly alter digoxin PK. GLSM ratios for C max , trough plasma concentration, and AUC during a dosing interval for digoxin versus esaxerenone + digoxin were 1.130, 1.088, and 1.072, respectively. Conclusions No drug–drug interactions are expected during combination therapy with esaxerenone and either amlodipine or digoxin, based on a lack of any clinically relevant PK changes. Trial registration Studies 1 and 2: JapicCTI-163379 (registered on 20 September 2016); Study 3: JapicCTI-163443 (registered on 24 November 2016).