In vitro and physiologically-based pharmacokinetic based assessment of drug-drug interaction potential of canagliflozin.

Article Details

Citation

Mamidi RNVS, Dallas S, Sensenhauser C, Lim HK, Scheers E, Verboven P, Cuyckens F, Leclercq L, Evans DC, Kelley MF, Johnson MD, Snoeys J

In vitro and physiologically-based pharmacokinetic based assessment of drug-drug interaction potential of canagliflozin.

Br J Clin Pharmacol. 2017 May;83(5):1082-1096. doi: 10.1111/bcp.13186. Epub 2016 Dec 20.

PubMed ID
27862160 [ View in PubMed
]
Abstract

AIMS: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed. METHODS: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interactions in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin. RESULTS: Canagliflozin was primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein-2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC50 ) of CYP3A4 (27 mumol l (-1) , standard error [SE] 4.9), CYP2C9 (80 mumol l (-1) , SE 8.1), CYP2B6 (16 mumol l(-1) , SE 2.1), CYP2C8 (75 mumol l (-1) , SE 6.4), P-glycoprotein (19.3 mumol l (-1) , SE 7.2), and multidrug resistance-associated protein-2 (21.5 mumol l (-1) , SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S-warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration-time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80-1.25. CONCLUSIONS: In vitro DDI followed by a predictive or PBPK approach was applied to determine DDI potential of canagliflozin. Overall, canagliflozin is neither a perpetrator nor a victim of clinically important interactions.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
CanagliflozinP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Canagliflozin
Efavirenz
The serum concentration of Canagliflozin can be decreased when it is combined with Efavirenz.
Canagliflozin
Butalbital
The serum concentration of Canagliflozin can be decreased when it is combined with Butalbital.
Canagliflozin
Pentobarbital
The serum concentration of Canagliflozin can be decreased when it is combined with Pentobarbital.
Canagliflozin
Secobarbital
The serum concentration of Canagliflozin can be decreased when it is combined with Secobarbital.
Canagliflozin
Methohexital
The serum concentration of Canagliflozin can be decreased when it is combined with Methohexital.