Construction of physiologically based pharmacokinetic model to predict CYP1A autoinduction by multi-kinase inhibitor TSU-68 based on in vitro induction kinetics

Autoinduction, which is enzyme induction promoted by a substrate drug, may lead to difficulties in achieving therapeutic efficacy owing to reduced plasma drug exposure. However, quantifying the extent of autoinduction in humans before clinical application remains challenging. TSU-68, a multi-kinase inhibitor, demonstrated reduced plasma concentrations to half of its initial levels following repeated oral dosing in clinical studies, and non-clinical research suggested its CYP1A autoinduction potential. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model of TSU-68 to quantitatively describe CYP1A autoinduction. An in vitro human hepatocytes induction study demonstrated a TSU-68 concentration-dependent increase in CYP1A1/2 mRNA expressions and enzyme activities. Notably, CYP1A1 enzyme activity induction kinetics differed from those of CYP1A2, and the reduction in TSU-68 concentration in the hepatocyte culture medium was more rapid at higher TSU-68 concentrations. Based on these findings, a mathematical model describing in vitro CYP1A induction was constructed, followed by the construction of a PBPK model incorporating the in vitro mathematical model, demonstrating the capture of observed clinical data after repeated doses. These results underscore the significance of considering in vitro induction kinetics, including changes in CYP1A enzyme and drug concentrations in the medium, to quantitatively predict CYP1A autoinduction.

CYP1A; Hepatocytes; Induction; PBPK model; Pharmacokinetics; Protein binding.