Prediction And Verification Of The Pharmacokinetics Of Methotrexate In Children Based On Physiologically Based Modeling

Objectives:To establish a physiologically based pharmacokinetic model(PBPK) for the prediction and validation of the pharmacokinetics of MTX in children and patient in renal dysfunction.Methods:A HPLC method for the determination of MTX in plasma was established and validated to study its pharmacokinetics in rats, rabbits and beagle dogs after single injection of MTX. Parameters of unbound fraction in plasma and blood-to-plasma concentration ratio were collected and used for the stimulated PBPK model to predict the pharmacokinetics of MTX in children and patients in renal dysfunction by species extrapolation. The results were then validated by the clinical data.Results:A simple and stable HPLC method was established to determine the concentration of MTX in plasma, the standard curve regression equation was Y=3.46×10-1X-5.5×10-3(r=0.9998) and the linear range was in 0.0512-50μ·gmL-1, the LLOQ was 0.05μg·mL-1. After single injection of MTX in rats, rabbit and dog, Cmax were (88.70± 11.60), (123.84±23.17) and (50.57±9.76) μg·mL-1; AUC(o-t) were (47.94±9.33), (79.02±11.23) and (67.88±10.32)mg·h·L-1; t1/2 were (2.12±0.24), (0.56±0.10) and (1.48±0.09)h; CL were (1.07±0.22), (0.39±0.06) and (0.29±0.02)L·h-1·kg-1; fup were 49%, 50%,39%; Rbp were 0.52,0.58,0.57, respectively. AUC predicted/observed ratio were less than 2 fold error in animals (<1.3 fold-error), while, it’s 74.75% in human and 80.72% in children.Conclusions:The PBPK model was reasonable in pharmacokinetic prediction both for animals and human, which was beneficial in improving clinical drug using, decreasing ADR and increasing efficiency.