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

摘要

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 24h ) with area under the concentration–time curve from time of dosing to 24 h after administration (AUC 24h ) 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 24h and ΔUGE 24h were 5417 (3229–8775) ng·h/mL and 85 (51–145) g, respectively. The simulation also suggested a 1.17‐fold increase in AUC 24h of ipragliflozin and a 0.76‐fold in ΔUGE 24h 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.