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

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 (Cmax) and time to Cmax 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 Cmax, 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 Cmax, 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).

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 (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.

Evaluation of Assay Sensitivity and the Concentration-Effect Relationship of Moxifloxacin in a QT/QTc Study in Japan.

To investigate the potential for a QT/QTc study in Japan, a randomized, single-blind, crossover study was conducted using moxifloxacin in 64 healthy Japanese male volunteers. A 12-lead Holter electrocardiogram was used to test a relatively small population at each of 4 incorporated clinical research units to confirm the assay sensitivity and efficiency. Moxifloxacin (400 mg) significantly prolonged QT intervals, as previously reported, with small variations in this study. In addition, the placebo-adjusted mean QTcF changes from predose baseline showed that the lower bounds of the 1-sided 95% confidence interval exceeded 5 milliseconds at all of the clinical research units. The data also indicated statistically significant concentration-QT relationships in 3 of the 4 research units by separate analysis. These findings and the small amount of variability in this study suggest the feasibility of conducting a high-quality QT/QTc study in Japan.

Measurement of drug concentration in the stomach after intragastric administration of drug solution to healthy volunteers: analysis of intragastric fluid dynamics and drug absorption.

PURPOSE: To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution. METHODS: Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol. RESULTS: Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2 min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4-133 mL with an average of 42 mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine. CONCLUSIONS: This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.