Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants.
Int J Clin Pharmacol Ther
; 53(2): 129-38, 2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25500487
ABSTRACT
OBJECTIVE:
To evaluate the pharmacokinetics of oral canagliflozin and its O-glucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated.METHODS:
In this open-label, single- (day 1) and multiple-dose (days 4-9), parallel-group, phase 1 study, 27 healthy participants were randomized into three groups (111) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre-pecified timepoints on days 1, 9, and 10.RESULTS:
Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination half-lives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI) 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed.CONCLUSION:
Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiofenos
/
Inibidores do Transportador 2 de Sódio-Glicose
/
Glucosídeos
Tipo de estudo:
Clinical_trials
Limite:
Adult
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article