A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects.

Abstract

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments.