The exposure-effect-toxicity correlation of docetaxel and magnesium isoglycyrrhizinate in non-small cell lung tumor-bearing mice

Abstract

To take full advantage of combination therapy of Docetaxel (DTX) and Magnesium isoglycyrrhizinate (MGIG), the pharmacokinetic- pharmacodynamic- toxicodynamics (PK-PD-TD) interaction of DTX and MGIG in non-small cell lung tumor-bearing mice was investigated in the present study. A model, an integrated semi-mechanistic PK-PD-TD, was established for elucidating the exposure-effect-toxicity relationship between DTX and MGIG. A tumor growth and a transit compartmental system were applied to imitate the growth and death of tumor cell. An indirect model with precursor-dependence was induced to clarify the temporal relationship between liver injury and drug exposure. No PK interaction between DTX and MGIG in plasma, liver and tumor was observed. In PD and TD results, MGIG had no antitumoral activity on non-small cell lung carcinoma, while it showed a strong hepatoprotection on DTX-induced liver injury. The PK-PD parameters of anti-tumor effect were related with the tumor growth characteristics, the kinetics of the tumor death and drug potency. In the PK-TD model, it was estimated about the elevation rate of ALT after DTX challenge in hepatocytes as well as plasma. MGIG reduced the DTX-induced ALT release rate from hepatocyte efficiently. Based on parameters estimated via PK-PD-TD correlation, the model successfully predicted the tumor growth kinetics and hepatoprotection at different dose regimes. Therefore, this prospective model might provide an alternative approache to the optimization of new experiment design.

Keywords: Docetaxel; Drug-induced liver injury; Magnesium isoglycyrrhizinate; Pharmacokinetic-pharmacodynamic-toxicodynamics model.