Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects.
Br J Clin Pharmacol
; 86(10): 2070-2079, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32250463
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rifampina
/
Itraconazol
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Humans
/
Male
País/Região como assunto:
Asia
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Japão