A physiologically based pharmacokinetic and pharmacodynamic model for disposition of FF-10832

This study aimed to quantitatively clarify the critical factors responsible for the superior antitumor efficacy of a liposomal gemcitabine (2,2-difluorodeoxycytidine; dFdC) formulation, FF-10832, compared with dFdC. The underlying hypothesis is the different exposure of tumors to its active metabolite, dFdC triphosphate (dFdCTP), between the two formulations. Therefore, physiologically based pharmacokinetic and pharmacodynamic (PBPK/ PD) models for encapsulated and unencapsulated dFdC were constructed considering the tumor dFdCTP con-centration as an index of antitumor activity. To estimate drug the parameters, the time profiles of encapsulated and unencapsulated dFdC in the blood and those of dFdC and dFdCTP in tumors were measured following the intravenous bolus administration of FF-10832 or dFdC. dFdC metabolism and transport in the liver S9 fraction and isolated hepatocytes, respectively, were experimentally determined. The tumor growth curve in a mouse xenograft model following the administration of FF10832 and dFdC was also used to construct the PD model. The sensitivity analysis of the PBPK/PD model revealed the critical factors affecting antitumor efficacy, which included the total and intratumor tissue uptake clearances for liposomal formulation and the cytidine deaminase and deoxycytidine deaminase activities in tumors. Thus, these parameters are potential biomarkers for predicting the efficacy of the liposomal formulation of dFdC.

Automated summary

This study aimed to quantitatively investigate the differences in antitumor efficacy between a liposomal gemcitabine formulation and conventional gemcitabine. The study found that the exposure of tumors to the active metabolite of gemcitabine was a critical factor in determining the antitumor efficacy. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models were constructed to analyze the differences between encapsulated and unencapsulated gemcitabine. The models revealed specific parameters that could serve as potential biomarkers for predicting the efficacy of the liposomal gemcitabine formulation.