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

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.,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 interaction in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of CYP inhibition by canagliflozin.,Canagliflozin was primarily metabolized by UGT1A9 and UGT2B4 enzymes. Canagliflozin was a substrate of efflux transporters (Pgp, BCRP, and MRP2) but was not a substrate of uptake transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC ) of CYP3A4 (27 μM, SE 4.9), CYP2C9 (80 μM, SE 8.1), CYP2B6 (16 μM, SE 2.1), CYP2C8 (75 μM, SE 6.4), Pgp (19.3 μM, SE 7.2), and MRP2 (21.5 μM, SE 3.1). Basic models recommended in DDI guidelines (USFDA and EMA) 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 AUC and C ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80-1.25.,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.