2021 - Online - In the cloud

PAGE 2021: Clinical Applications
Enrica Mezzalana

Population pharmacokinetic modelling and simulation of imeglimin in type 2 diabetes patients to support dose recommendations to patients with renal impairment

Enrica Mezzalana (2), Yoshiko Tomita (1), Emma Hansson (2), Florent Mazuir (3), Gustaf Wellhagen (2), Qing Xi Ooi (2), Atsushi Kitamura (1), Daisuke Nemoto (1), Sebastien Bolze (3)

(1) Sumitomo Dainippon Pharma Co, Ltd, Osaka, Japan, (2) Pharmetheus AB, Uppsala, Sweden, (3) Poxel SA, Lyon, France

Introduction: Imeglimin is a novel first-in class oral antidiabetic drug to treat type 2 diabetes (T2DM) [1]. Imeglimin is not metabolized but it is eliminated unchanged into urine [2]. Thus, a dosage reduction may be required in renally impaired patients. Phase 2b studies showed that optimal dose was 1000 mg BID in Japanese T2DM patients [3] and 1500 mg BID in Western T2DM patients [4] and slightly higher imeglimin exposures were observed in Japanese vs Western T2DM patients.

Objectives: The objective of this population pharmacokinetic (PK) analysis was to describe the PK characteristics of imeglimin following single and repeated oral administration of imeglimin in healthy volunteers and T2DM patients with different degrees of chronic kidney disease (CKD) and to identify covariates of clinical relevance.

Methods: Data from four Phase I studies, four Phase II studies and one Phase III study was used for the PK model development. Moreover, two additional Phase III studies were used for external evaluation of the PK model. Nonlinear mixed effects modelling was conducted using NONMEM v 7.3.0 [5].

Simulations of imeglimin area under the curve (AUC) in Japanese patients with CKD stage G3a (45 ≤ eGFR < 60 mL/min/1.73 m2), G3b (30 ≤ eGFR < 45 mL/min/1.73 m2) and G4 (15 ≤ eGFR < 30 mL/min/1.73 m2) were conducted based on the final population PK model. Japanese patients were sampled randomly with replacement to generate 1000 covariate vectors (termed reference subjects). The reference subjects were duplicated with eGFR replaced by eGFR sampled from a uniform distribution with minimum and maximum values set to the limits of the CKD stages of interest. To adjust for the known increase in age with CKD stage, the mean age was increased based on literature data in Japanese CKD patients [6][7][8].

Similarly, simulations of AUC in Japanese and Western patients were performed by sampling patients’ covariates from relevant studies in Japanese and Western T2DM patients. The Western reference subjects were duplicated (i) with similar eGFR distribution and (ii) with similar eGFR and body weight distributions as in the Japanese reference patients.

Results: The analysis dataset for PK model development contained 8256 PK observations from 867 individuals with a median age of 59.0 (range 20.0 - 80.0) years, body weight of 77.0 (range 35.6 - 148) kg, and estimated glomerular filtration rate (eGFR) of 81.4 (range 14.1 - 152) ml/min/1.73m2. The subjects were mainly male (56.9%), Western (55.6%), with CKD stage 2 (49.0%).

The imeglimin population PK was described by a two-compartment model with first-order absorption with a lag time and a first-order elimination from the central compartment. Interindividual variability (IIV) terms were supported on first-order absorption rate constant (ka), relative bioavailability (F), central volume of distribution (Vc), peripheral volume of distribution (Vp) and clearance (CL) with a correlation between CL and F.

Several covariates were identified as significant predictors for imeglimin PK. Lower body weight, higher age, and lower eGFR all lead to lower CL while higher dose leads to lower F. Japanese was associated with lower inter-compartmental clearance (Q). Among these covariates, eGFR had the largest impact on imeglimin exposure.

Simulations of AUC in T2DM Japanese patients with moderate to severe renal impairment suggested that imeglimin dose should be reduced to 500 mg twice daily (BID) for patients with eGFR ranging from 15 to 45 mL/min/1.73 m2.

Simulations for Japanese and Western T2DM patients showed that the difference in plasma AUC between these populations at the same dose was mainly driven by eGFR differences (+15.24 mL/min/1.73 m2 in Western).

Conclusions:  The proposed model was able to characterize imeglimin PK in T2DM patients. Simulations were used to derive expected exposures in moderate/severe renal impaired patients and to provide further insights in potential differences between Japanese and Western populations.

[1] Dubourg, J., Fouqueray, P., Thang, C., Grouin, J. M., & Ueki, K. Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial. Diabetes Care 44(4), 952-959 (2021).
[2] Clémence C, Fouqueray P, Sébastien B. In Vitro Investigation, Pharmacokinetics, and Disposition of Imeglimin, a Novel Oral Antidiabetic Drug, in Preclinical Species and Humans. Drug Metabolism and Disposition. 48(12), 1330-46 (2020).
[3] Dubourg, J., Ueki, K., Grouin, J. M., & Fouqueray, P. Efficacy And Safety Of Imeglimin In Japanese Patients With Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Phase 2b Trial. Diabetes, Obesity and Metabolism 23(3):800-810 (2021).
[4] Johansson, K.S., Brønden, A., Knop, F.K. and Christensen, M.B. Clinical pharmacology of imeglimin for the treatment of type 2 diabetes. Expert opinion on pharmacotherapy, 21(8), pp.871-882 (2020).
[5] Beal SL, Sheiner LB, Boeckmann AJ and Bauer RJ, 2014, NONMEM User’s Guides. (1989-2014) Icon Development Solutions, Ellicott City, MD, USA
[6] Haneda, M. et al. Influence of renal function on the 52-week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin. Ther. 38, 66-88 (2016).
[7] Haneda, M. et al. Safety and efficacy of teneligliptin in patients with type 2 diabetes mellitus and impaired renal function: Interim report from post-marketing surveillance. Diabetes Ther. 9, 1083-1097 (2018).
[8] Kobayashi, K. et al. Retrospective analysis of effects of sodium-glucose co-transporter 2 inhibitor in Japanese type 2 diabetes mellitus patients with chronic kidney disease. Diab. Vasc. Dis. Res. 16, 103–107 (2019).

Reference: PAGE 29 (2021) Abstr 9668 [www.page-meeting.org/?abstract=9668]
Poster: Clinical Applications
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