Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

Article Details

Citation

Devineni D, Vaccaro N, Murphy J, Curtin C, Mamidi RN, Weiner S, Wang SS, Ariyawansa J, Stieltjes H, Wajs E, Di Prospero NA, Rothenberg P

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

Int J Clin Pharmacol Ther. 2015 Feb;53(2):115-28. doi: 10.5414/CP202158.

PubMed ID
25407255 [ View in PubMed
]
Abstract

OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. METHODS: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). RESULTS: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. CONCLUSION: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CanagliflozinUDP-glucuronosyltransferase 1-9ProteinHumans
Unknown
Substrate
Details
CanagliflozinUDP-glucuronosyltransferase 2B4ProteinHumans
Unknown
Substrate
Details
ProbenecidCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
CanagliflozinP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Canagliflozin
Phenytoin
The serum concentration of Canagliflozin can be decreased when it is combined with Phenytoin.
Canagliflozin
Fosphenytoin
The serum concentration of Canagliflozin can be decreased when it is combined with Fosphenytoin.
Canagliflozin
Rifampicin
The serum concentration of Canagliflozin can be decreased when it is combined with Rifampicin.
Canagliflozin
Carbamazepine
The metabolism of Canagliflozin can be increased when combined with Carbamazepine.