Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients with Type 1 and Type 2 Diabetes Mellitus.

Purpose: To characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM. Methods: The PK (AUC(24h) of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (E-max) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM. Findings: Data from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC(24h) of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean E-max and AUC(24h) producing 50% of E-max (EX50) were 45.1 mL/min (95% CI, 37.0-53.2 mL/min) and 2160 ng.h/mL (95% CI, 929-3390 ng.h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model. Implications: The PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. (c) 2020 Elsevier Inc.