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From Target Selection to the Minimum Acceptable Biological Effect Level for Human Study: Use of Mechanism-based PK/PD Modeling to Design Safe and Efficacious Biologics

Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

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Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

Content Provider	Springer Nature Link
Author	Krishna, Rajesh Bergman, Arthur J. Green, Michele Dockendorf, Marissa F. Wagner, John A. Dykstra, Kevin
Copyright Year	2011
Abstract	A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase III confirmatory program. Nonlinear mixed effects PK/PD models were initially developed based on data obtained from multiple phase I studies and later were updated with data from a phase IIb study. The population pharmacokinetic model described differences between the liquid-filled capsule used in phase I and phase IIb and the hot-melt extruded (HME) tablet formulation introduced in phase III, allowing for bridging of the two formulations, and quantified the complex relationship of apparent anacetrapib bioavailability with subject meal intake. Proportional E $_{max}$ models quantified the relationships between anacetrapib trough concentration and lipoprotein effects (LDL-C and HDL-C), with covariate effects of study population (normal volunteers vs. patients), and co-administration with HMG-CoA reductase inhibitor (“statin”). The interaction between anacetrapib and atorvastatin suggested pharmacological independence, i.e., that when given together, each agent exerts the same proportional lipid effect observed from monotherapy. Clinical trial simulation was used to examine the robustness of the effects to random dietary indiscretion, and found that the results were robust as long as patients generally adhered to a low-fat diet. These results allowed the selection of the 100 mg dose with the HME formulation for phase III development even though this dose and formulation were not specifically studied in a phase IIb trial.
Starting Page	179
Ending Page	190
Page Count	12
File Format	PDF
ISSN	12341234
Journal	The AAPS Journal
Volume Number	13
Issue Number	2
e-ISSN	15507416
Language	English
Publisher	Springer US
Publisher Date	2011-02-23
Publisher Institution	American Association of Pharmaceutical Scientists
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	anacetrapib cetp inhibition clinical trial simulation modeling Pharmacy Biotechnology Biochemistry Pharmacology/Toxicology
Content Type	Text
Resource Type	Article

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Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?

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Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib.

A molecular dynamics investigation on the inhibition mechanism of cholesteryl ester transfer protein by Anacetrapib

Docking and receptor-based QSAR approaches for modeling of CETP inhibitors

Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

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