Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction. (13th April 2014)

• Record Type: Journal Article
• Authors: Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing
• Is Part Of: Biopharmaceutics & drug disposition. Volume 35:Number 5(2014:Jul.)
• Page Start: 296
• Page End: 307
• Publication Date: 2014-04-13
• Subjects: Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1897
• Languages: English
• ISSNs: 0142-2782

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>YQA‐14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA‐14, then to simulate the clinical PK of YQA‐14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA‐14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human <italic>in vitro</italic> ADME data obtained from <italic>in vitro</italic> studies. The study data showed that YQA‐14 is a basic lipophilic compound, with rapid absorption (<italic>T</italic><sub>max</sub> ~ 1 h) in both rats and dogs. Liver microsomal clearances and <italic>in vivo</italic> clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA‐14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA‐14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic. Copyright © 2014 John Wiley & Sons, Ltd.</p> </abstract>