Table 2.

Simulation trial design to evaluate clinical drug–drug interaction (DDI) cytochrome P450 (CYP) inhibition of canagliflozin

Trial description and purpose	Study design outline of simulation trials
Simulation of canagliflozin pharmacokinetics after single oral administration of 300 mg canagliflozin to healthy subjects. Purpose is to verify the performance of PBPK model	Ten trials of nine virtual male healthy subjects were simulated with a body weight between 62 and 94 kg to match the population of a clinical study in healthy subjects 13. Covariates of weight, age and sex were taken into consideration.
Simulation of DDI between 300 mg oral canagliflozin and a single dose of 40 mg simvastatin (CYP3A4 substrate)	Trial design consisted of 10 trials of 10 virtual healthy subjects who received an oral dose of 40 mg simvastatin with or without canagliflozin 300 mg QD. Simvastain was dosed without canagliflozin on day 1. Canagliflozin was dosed once daily from day 2 to day 7. One dose of 40 mg simvastatin was coadministered with canagliflozin on day 7. Simulated pharmacokinetic profiles were obtained for simvastatin with and without canagliflozin.
Simulation of DDI between 300 mg oral canagliflozin and a single dose of 15 mg S‐warfarin (CYP2C9 substrate)	Trial design consisted of 2 trials of 10 virtual healthy subjects who received an oral dose of 15 mg S‐warfarin with or without canagliflozin 300 mg QD. S‐warfarin was dosed without canagliflozin on day 1. Canagliflozin was dosed once daily from day 2 to day 12. One dose of 15 mg S‐warfarin was coadministered with canagliflozin on day 12. Simulated pharmacokinetic profiles were obtained for S‐warfarin with and without canagliflozin.
Simulation of DDI between 300 mg oral canagliflozin and a single dose of 150 mg bupropion (CYP2B6 substrate)	Trial design consisted of 10 trials of 10 virtual healthy subjects who received an oral dose of 150 mg with or without canagliflozin 300 mg QD. Bupropion was dosed without canagliflozin on day 1. Canagliflozin was dosed once daily from day 2 to day 6. One dose of 150 mg bupropion was coadministered with canagliflozin on day 6. Simulated pharmacokinetic profiles were obtained for bupropion with and without canagliflozin.
Simulation of DDI between 300 mg oral canagliflozin and a single dose of 0.25 mg repaglinide (CYP2C8 substrate)	Trial design consisted of 10 trials of 10 virtual healthy subjects who received an oral dose of 0.25 mg with or without canagliflozin 300 mg QD. Repaglinide was dosed without canagliflozin on day 1. Canagliflozin was dosed once daily from day 2 to day 6. One dose of 0.25 mg repaglinide was coadministered with canagliflozin on day 6. Simulated pharmacokinetic profiles were obtained for repaglinide with and without canagliflozin.

PBPK, physiologically‐based pharmacokinetic; QD, once daily