Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver
Creators: name: Nakayama, Keigo
name: Ito, Soichiro
name: Suzuki, Masahiro
name: Takubo, Hiroaki
name: Yamazaki, Hiroshi
name: Nomura, Yukihiro
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biochemistry
subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: 19999 Mathematical Sciences not elsewhere classified
subject: FOS: Mathematics
subject: FOS: Mathematics
subject: Plant Biology

description: In this study, total body clearance (CL<sub>t</sub>), volume of distribution at steady state (<i>V</i><sub>ss</sub>) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.On the basis of assumption that unbound intrinsic clearance (CL<sub>Uint</sub>) per liver weight in chimeric mice was equal to those in humans, CL<sub>t</sub> were predicted by substituting human liver blood flow and liver weights in well-stirred model. <i>V</i><sub>ss</sub> were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF<sub>Kp</sub>) in chimeric mice estimated from a difference between the observed and predicted <i>V</i><sub>ss</sub>. These physiological approaches showed high prediction accuracy for CL<sub>t</sub> and <i>V</i><sub>ss</sub> values in humans.We compared the predictability of CL<sub>t</sub> and <i>V</i><sub>ss</sub> determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL<sub>Uint</sub> and SF<sub>Kp</sub> obtained from chimeric mice.Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds. In this study, total body clearance (CL<sub>t</sub>), volume of distribution at steady state (<i>V</i><sub>ss</sub>) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. On the basis of assumption that unbound intrinsic clearance (CL<sub>Uint</sub>) per liver weight in chimeric mice was equal to those in humans, CL<sub>t</sub> were predicted by substituting human liver blood flow and liver weights in well-stirred model. <i>V</i><sub>ss</sub> were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF<sub>Kp</sub>) in chimeric mice estimated from a difference between the observed and predicted <i>V</i><sub>ss</sub>. These physiological approaches showed high prediction accuracy for CL<sub>t</sub> and <i>V</i><sub>ss</sub> values in humans. We compared the predictability of CL<sub>t</sub> and <i>V</i><sub>ss</sub> determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method. Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL<sub>Uint</sub> and SF<sub>Kp</sub> obtained from chimeric mice. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.