A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519.

Choon Ok Kim,Seunghoon Han,Sangil Jeon,Min Soo Park,Dong‐Seok Yim

doi:10.3390/pharmaceutics12060573

Abstract

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang’s distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia.

Highlights

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein consisting of 476 amino acids with a mass of 53 kDa [1]
There have been many efforts to modify the composition of the plasma lipoprotein favorably through inhibition of CETP activity [3]
CKD-519 is a potent, selective CETP inhibitor being developed for the treatment of dyslipidemia

Summary

Introduction

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein consisting of 476 amino acids with a mass of 53 kDa [1]. It mediates bidirectional transfers of cholesteryl ester and triglyceride between high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B-containing lipoproteins, such as very-low-density lipoprotein and low-density lipoprotein cholesterol (LDL-C) [2]. CKD-519 is a potent, selective CETP inhibitor being developed for the treatment of dyslipidemia. It is one of the cycloalkenyl benzene derivatives with a molecular weight of 601.60 g/mol (C31H34F7NO3) [4]. In the in vitro solubility test, CKD-519 was insoluble in deionized water and freely soluble in ethyl alcohol with its LogD of 7.4, and LogP is >5.0 at pH 7.4 [4,5]

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