Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

• DOI: 10.1111/cts.12747
• Publication Date: 2020-02-11T02:40:55Z
• Authors: Maria Garcia‐Crem...; Nicola Melillo; Iñaki F. Troconiz; Paolo Magni
• Keywords: Deoxycytidine kinase

The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2’,2’‐difluorodeoxycytidine (gemcitabine, dFdC), able describe concentrations dFdC metabolites in pancreatic tumor tissue dependence physiological and genetic patient characteristics, and, more general, explore capabilities limitations kind modeling strategy. A characterizing metabolic pathway (metabolic network) was developed using vitro literature data from two cancer cell lines. network time course extracellular intracellular concentrations. Moreover, physiologically‐based clinical profiles by enzymatic information available literature. This then coupled with active metabolite profile tissue. Finally, global sensitivity analysis performed identify parameters that mainly drive interindividual variability area under curve (AUC) plasma its (dFdCTP) From analysis, cytidine deaminase (CDA) concentration identified as main driver AUC variability, whereas CDA deoxycytidine kinase explained dFdCTP variability. However, lack vivo needed characterize key hampers development approach. Further studies better lines enzymes polymorphisms are encouraged refine validate current model.