Abstract
CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data.
Highlights
Dyslipidemia is defined as an elevated plasma low-density lipoprotein (LDL) or triglyceride (TG) level or a low plasma high-density lipoprotein (HDL) level [1]
Cholesteryl ester transfer protein (CETP) has become a target for the treatment of dyslipidemia, and CETP inhibitors are expected to be a powerful class of drugs for increasing HDL and decreasing LDL levels, which should help reduce the risk of atherosclerotic cardiovascular disease (CVD) [4,6,7]
The observed plasma concentration–time profiles by species and dosage regimens are presented as Figure 1, and the animal PK properties of CKD519 are summarized as the results from non-compartmental analysis (NCA) (Table 2)
Summary
Dyslipidemia is defined as an elevated plasma low-density lipoprotein (LDL) or triglyceride (TG) level or a low plasma high-density lipoprotein (HDL) level [1]. Large observational studies have reported a strong graded relationship between high LDL and/or low HDL levels and risk for atherosclerotic CVD [1,2,3]. Hydroxymethylglutaryl coenzyme A reductase (statin) is used as the gold standard for LDL-lowering therapy and has been shown to reduce the risk of CVD in humans. Even after the aggressive use of LDL-lowering drugs, the incidence of residual cardiovascular events remains high, which suggests the need to find additional approaches [3]. CETP has become a target for the treatment of dyslipidemia, and CETP inhibitors are expected to be a powerful class of drugs for increasing HDL and decreasing LDL levels, which should help reduce the risk of atherosclerotic CVD [4,6,7]
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