Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)
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...
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doaj-1a5302f7a2ed4f95a613b8550172d3462020-11-24T20:43:21ZengMDPI AGPharmaceutics1999-49232019-07-0111733610.3390/pharmaceutics11070336pharmaceutics11070336Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)Suein Choi0Seunghoon Han1Sangil Jeon2Dong-Seok Yim3PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaPIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaQ-fitter, Inc., Seoul 06199, KoreaPIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaCKD519, 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 <i>E</i><sub>max</sub> model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the <i>E</i><sub>max</sub> 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.https://www.mdpi.com/1999-4923/11/7/336CETP inhibitiondyslipidemiacholesteryl ester transfer proteinpharmacodynamicspharmacokineticsin vivo-in vitro extrapolation (IVIVE)first-in-humanallometric scalingprediction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Suein Choi Seunghoon Han Sangil Jeon Dong-Seok Yim |
spellingShingle |
Suein Choi Seunghoon Han Sangil Jeon Dong-Seok Yim Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) Pharmaceutics CETP inhibition dyslipidemia cholesteryl ester transfer protein pharmacodynamics pharmacokinetics in vivo-in vitro extrapolation (IVIVE) first-in-human allometric scaling prediction |
author_facet |
Suein Choi Seunghoon Han Sangil Jeon Dong-Seok Yim |
author_sort |
Suein Choi |
title |
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) |
title_short |
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) |
title_full |
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) |
title_fullStr |
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) |
title_full_unstemmed |
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP) |
title_sort |
quantitative prediction of human pharmacokinetics and pharmacodynamics of ckd519, a potent inhibitor of cholesteryl ester transfer protein (cetp) |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2019-07-01 |
description |
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 <i>E</i><sub>max</sub> model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the <i>E</i><sub>max</sub> 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. |
topic |
CETP inhibition dyslipidemia cholesteryl ester transfer protein pharmacodynamics pharmacokinetics in vivo-in vitro extrapolation (IVIVE) first-in-human allometric scaling prediction |
url |
https://www.mdpi.com/1999-4923/11/7/336 |
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