Journal
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
Volume 45, Issue 5, Pages 733-746Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10928-018-9603-z
Keywords
Physiologically-based pharmacokinetic model; Pharmacodynamics; Gemcitabine; Birinapant; Drug combination; Pancreatic cancer xenografts
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Funding
- National Institutes of Health [R01 GM24211, R01 CA198096]
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The anticancer effects of combined gemcitabine and birinapant were demonstrated as synergistic in PANC-1 cells in vitro. In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity. The network model developed for drug effects in the in vitro cell cultures was applied successfully to link the in vivo tumor drug concentrations with tumor growth inhibition, incorporating more mechanistic features and accounting for disparate drug interaction outcomes in vitro and in vivo.
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