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Open AccessArticle

Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)

by 1,2,†, 1,2,3,†, 3 and 1,2,3,*
1
PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
2
Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul 06591, Korea
3
Q-fitter, Inc., Seoul 06199, Korea
*
Author to whom correspondence should be addressed.
Both authors equally contributed to this manuscript.
Pharmaceutics 2019, 11(7), 336; https://doi.org/10.3390/pharmaceutics11070336
Received: 13 June 2019 / Revised: 3 July 2019 / Accepted: 9 July 2019 / Published: 15 July 2019
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. View Full-Text
Keywords: CETP inhibition; dyslipidemia; cholesteryl ester transfer protein; pharmacodynamics; pharmacokinetics; in vivo-in vitro extrapolation (IVIVE); first-in-human; allometric scaling; prediction CETP inhibition; dyslipidemia; cholesteryl ester transfer protein; pharmacodynamics; pharmacokinetics; in vivo-in vitro extrapolation (IVIVE); first-in-human; allometric scaling; prediction
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Choi, S.; Han, S.; Jeon, S.; Yim, D.-S. Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP). Pharmaceutics 2019, 11, 336.

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