Pharmacokinetic/pharmacodynamic modelling of intracellular gemcitabine triphosphate accumulation: translating in vitro to in vivo

A detailed intracellular (IC) model describing the pharmacokinetics (PK) of gemcitabine (2´,2´-difluoro-2´-deoxycytidine, dFdC) was developed and linked to a systemic plasma dFdC PK model. Based on in vivo PK, pharmacodynamic (PD) effect predictions were made using a simplified cell-cycle model (CCM). A reduced-order compartmental model describing the IC metabolism of dFdC was fit to in vitro data taken from the literature to estimate the kinetic parameters of gemcitabine triphosphate (dFdCTP) generation and elimination in leukaemia cells. For comparison with in vivo patient data, the proposed detailed IC model, coupled with the systemic PK model and the CCM PD model, was simulated; Monte Carlo randomisation of the parameter vector was used to simulate interpatient variability. This comparison of model-generated IC dFdCTP concentrations with literature values in peripheral blood mononuclear cells (PBMCs) revealed qualitative and quantitative agreement. A tumour interstitial compartment connecting the plasma and IC models allowed prediction of solid tumour dFdCTP concentration.