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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).

Pharmacokinetic interactions of esaxerenone with amlodipine and digoxin in healthy Japanese subjects