Pharmacokinetic and pharmacodynamic modelling for renal function dependent urinary glucose excretion effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, both in healthy subjects and patients with type 2 diabetes mellitus.

Aims: To provide a model-based prediction of individual urinary glucose excretion (UGE) effect of ipragliflozin, we constructed a pharmacokinetic/pharmacodynamic (PK/PD) model and a population PK model using pooled data of clinical studies.

Methods: A PK/PD model for the change from baseline in UGE for 24 hours (ΔUGE ) with area under the concentration-time curve from time of dosing to 24 h after administration (AUC ) of ipragliflozin was described by a maximum effect model. A population PK model was also constructed using rich PK sampling data obtained from 2 clinical pharmacology studies and sparse data from 4 late-phase studies by the NONMEM $PRIOR subroutine. Finally, we simulated how the PK/PD of ipragliflozin changes in response to dose regime as well as patients' renal function using the developed model.

Results: The estimated individual maximum effect were dependent on fasting plasma glucose and renal function, except in patients who had significant UGE before treatment. The PK of ipragliflozin in type 2 diabetes mellitus (T2DM) patients was accurately described by a 2-compartment model with first order absorption. The population mean oral clearance was 9.47 L/h and was increased in patients with higher glomerular filtration rates and body surface area. Simulation suggested that medians (95% prediction intervals) of AUC and ΔUGE were 5417 (3229-8775) ng·h/mL and 85 (51-145) g, respectively. The simulation also suggested a 1.17-fold increase in AUC of ipragliflozin and a 0.76-fold in ΔUGE in T2DM patients with moderate renal impairment compared to those with normal renal function.

Conclusions: The developed models described the clinical data well, and the simulation suggested mechanism-based weaker antidiabetic effect in T2DM patients with renal impairment.