Junko Toyoshima and Masako Saito
Astellas Pharma Inc.
Introduction: Ipragliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor which inhibits the reabsorption of glucose from kidneys and increases urinary glucose excretion, thereby lowering the blood glucose concentration. Considering the unique mechanism of action, combined use of ipragliflozin with insulin expected to be efficacious for glycemic control in type 1 diabetes mellitus (T1DM) patients as well as in type 2 diabetes mellitus (T2DM) patients. A clinical pharmacology study was previously conducted to characterize the pharmacokinetics and pharmacodynamics of ipragliflozin doses of 25, 50, and 100 mg under concomitant use with insulin in Japanese T1DM patients [1]. Additionally, a similar clinical pharmacology study had been conducted with ipragliflozin doses at 50 and 100 mg in Japanese T2DM patients [2]. Pharmacometrics approach was performed to compare the exposure-response relationship and to set the dose regimen for the phase 3 study in T1DM patients.
Objectives: To characterize the exposure-response relationship for ipragliflozin in Japanese T1DM and T2DM patients and to provide the dose setting rationale for the phase 3 study in T1DM patients.
Methods: Data from two clinical pharmacology studies in T1DM and T2DM patients [1-2] was used to compare the relationships between exposure (area under the concentration-time curve for 24 hours: AUC24h) and response (pharmacodynamics effect: renal glucose clearance: CLr,glu) in T1DM and T2DM patients after ipragliflozin administration. The relationship was described by Emax model using NONMEM® (CLr,glu model). Next, to evaluate the observed FPG in T1DM patients, an empirical model which developed using data from three late phase clinical studies in T2DM patients [3] were applied for the simulation. In the model, the time course of FPG was modeled using a combined model with the disease progression and drug effect model (FPG model).
Results: Data from 42 T1DM and 28 T2DM patients were used to develop CLr,glu model. The exposure response relationship for ipragliflozin was well described with Emax model. As the result of covariate extrapolation, estimated glomerular filtration rate (eGFR) had a significant effect on Emax, while, diabetes type (T1DM/T2DM) was not significant on both Emax and EC50. Data from 589 T2DM patients was used to develop FPG model. The time-course of changes in FPG was described using a combination model of disease progression and drug effect. Disease progress curve was described using a model with exponential time course approaching a steady state. Drug effect was modeled using Emax model with an effect compartment model to describe the delay of response in FPG. Baseline FPG and renal function had significant impacts on Emax. The simulation results from FPG model well explained that the observed FPG in T1DM based on the difference at baseline.
Conclusions: The CLr,glu model and FPG model revealed the exposure-response relationship for ipragliflozin was comparable between T1DM and T2DM patients, and supported the same dose regimen used for T2DM patients in T1DM patients.
References:
[1] Kadokura T, Akiyama N, Kashiwagi A, et al. Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. Diabetes Res Clin Pract. 2014;106:50-6.
[2] Kaku K, Isaka H, Toyoshima J, Sakatani T. Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial. Diabetes Obes Metab. 2019; 21(6):1445-1454.
[3] Saito M, Kaibara A, Kadokura T, et al. Model-based prediction of the long-term glucose lowering effects of ipragliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in Patients with Type 2 Diabetes Mellitus. Diabetes Therapy. In press.
Reference: PAGE () Abstr 9278 [www.page-meeting.org/?abstract=9278]
Poster: Drug/Disease Modelling - Endocrine