Population pharmacokinetic analysis of evogliptin in subjects with varying degrees of renal function
Sang-In Park (1), Jaeseong Oh (1), SeungHwan Lee (1), Kyung-Sang Yu (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM) patients. Renal impairment, one of the complications of T2DM, can alter the pharmacokinetics (PK) of evogliptin [1]. The objective of this study was to develop a population PK model of evogliptin in subjects with varying degrees of renal function and to evaluate the effects of the factors including renal function on the PK of evogliptin.
Methods: Plasma concentrations of evogliptin obtained from 30 subjects who received a single oral dose of 5 mg evogliptin were included for population PK analysis. The analysis was performed using non-linear mixed-effects modelling as implemented in NONMEM version 7.3. Renal function of the subjects were estimated based on the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula. Covariates including eGFR, body weight, age, and height were evaluated and the final model was selected based on decrease in objective function, diagnostic plots, and visual predictive checks.
Results: A two-compartmental model with first order-absorption was selected as the final PK model. Inter-individual variability (IIV) was modeled using an exponential error model and residual variability was modeled using a combined proportional and additive random effects model. The eGFR had a significant influence on apparent clearance (CL/F), and both the eGFR and body weight had a significant influence on apparent volume of distribution for central compartment (V2/F) which were described in the final model as follows: CL/F (L/h) = 18.8 × (eGFR/63.7)0.529; V2/F (L) = 757 × (body weight/61.4)0.667 × (eGFR/63.7)0.284. The typical value of absorption rate constant (Ka) was 1.03 h-1. The IIV (CV%) for CL/F, V2/F, and Ka were 27.3%, 18.0%, and 53.2%, respectively. Model evaluation by goodness-of-fit plots and visual predictive checks suggested that the proposed model adequately described the observed data.
Conclusions: The population PK model for evogliptin was used successfully to select the significant covariates for the PK parameters of evogliptin. This model can be utilized to guide evogliptin therapy by explaining the effects of renal impairments on the PK of evogliptin.
References:
[1] J. Oh, A. H. Kim, S. Lee, H. Cho, Y. S. Kim, M. Y. Bahng, S. H. Yoon, J. Y. Cho, I. J. Jang, and K. S. Yu, Diabetes, Obesity and Metabolism (2016).