title: Translational modeling and simulation approaches for molecularly targeted small molecule anticancer agents from bench to bedside.
abstract: BACKGROUND
  Recent advances in molecular biology have enabled personalized cancer therapies with molecularly targeted agents (MTAs), which offer a promising future for cancer therapy. Dynamic modeling and simulation (M&S) is a powerful mathematical approach linking drug exposures to pharmacological responses, providing a quantitative assessment of in vivo drug potency. Accordingly, a growing emphasis is being placed upon M&S to quantitatively understand therapeutic exposure-response relationships of MTAs in nonclinical models.
  
  
  METHODS
  An overview of M&S approaches for MTAs in nonclinical models is presented with discussion about mechanistic extrapolation of antitumor efficacy from bench to bedside. Emphasis is placed upon recent advances in M&S approaches linking drug exposures, biomarker responses (e.g. target modulation) and pharmacological outcomes (e.g. antitumor efficacy).
  
  
  CONCLUSIONS
  For successful personalized cancer therapies with MTAs, it is critical to mechanistically and quantitatively understand their exposure-response relationships in nonclinical models, and to logically and properly apply such knowledge to the clinic. Particularly, M&S approaches to predict pharmacologically active concentrations of MTAs in patients based upon nonclinical data would be highly valuable in guiding the design and execution of clinical trials. Proactive approaches to understand their exposure-response relationships could substantially increase probability of achieving a positive proof-of-concept in the clinic.
authors.affiliation: a Pharmacokinetics, Dynamics & Metabolism , Pfizer Worldwide Research & Development , San Diego , CA , USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: a Pharmacokinetics, Dynamics & Metabolism , Pfizer Worldwide Research & Development , San Diego , CA , USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Spilker
authors.affiliation: a Pharmacokinetics, Dynamics & Metabolism , Pfizer Worldwide Research & Development , San Diego , CA , USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D008954:Models, Biological; D008967:Molecular Biology / Q000379:methods; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D057285:Precision Medicine; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: D000970:Antineoplastic Agents
keywords: Cancer; drug-disease modeling; mathematical modeling; modeling and simulation; molecularly targeted agents; oncology; pharmacokinetic-disease modeling; pharmacokinetic-pharmacodynamic modeling; targeted cancer therapies; translational pharmacology; tyrosine kinase inhibitor