The class
Preclinical pharmacokinetic modeling predicts a human dose of the CETP inhibitor CKD519 before phase 1 data revealed a gap (Pharmaceutics 2019)
Original title: Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)
CKD519, a selective CETP inhibitor in development for hypercholesterolemia and mixed hyperlipidemia, was given intravenously and orally to hamsters, rats and monkeys to build interspecies pharmacokinetic models using allometric scaling, which were then linked to a same-in-class drug's Emax pharmacodynamic model to predict human dosing. A two-compartment model with Weibull-type absorption and sigmoid Emax bioavailability best described the preclinical data, and the resulting simulation estimated an efficacious human dose of 25 mg in a 60 kg person. However, comparison with actual phase 1 clinical data revealed a large discrepancy in predicted versus observed bioavailability, highlighting the difficulty of predicting oral absorption from animal pharmacokinetic data alone.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.