Translational pharmacokinetic-pharmacodynamic modeling from nonclinical to clinical development: a case study of anticancer drug\t crizotinib.\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t

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Attrition risk related to efficacy is still a major reason why new chemical entities fail in clinical trials despite recently increased understanding of translational pharmacology. Pharmacokinetic-pharmacodynamic (PKPD) analysis is key to translating in vivo drug potency from nonclinical models to patients by providing a quantitative assessment of in vivo drug potency with mechanistic insight of drug action. The pharmaceutical industry is clearly moving toward more mechanistic and quantitative PKPD modeling to have a deeper understanding of translational pharmacology. This paper summarizes an anticancer drug case study describing the translational PKPD modeling of crizotinib\t an orally available\t potent small molecule inhibitor of multiple tyrosine kinases including anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (MET)\t from nonclinical to clinical development. Overall\t the PKPD relationships among crizotinib systemic exposure\t ALK or MET inhibition\t and tumor growth inhibition (TGI) in human tumor xenograft models were well characterized in a quantitative manner using mathematical modeling: the results suggest that 50% ALK inhibition is required for >50% TGI whereas >90% MET inhibition is required for >50% TGI. Furthermore\t >75% ALK inhibition and >95% MET inhibition in patient tumors were projected by PKPD modeling during the clinically recommended dosing regimen\t twice daily doses of crizotinib 250 mg (500 mg/day). These simulation results of crizotinib-mediated ALK and MET inhibition appeared consistent with the currently reported clinical responses. In summary\t the present paper presents an anticancer drug example to demonstrate that quantitative PKPD modeling can be used for predictive translational pharmacology from nonclinical to clinical development.\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t

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  • Administração Oral\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Animais\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Antineoplásicos/administração & dosagem\t\t\t
  • Antineoplásicos/farmacocinética\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Camundongos Nus\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Camundongos\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Carga Tumoral/efeitos de drogas\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Cálculos da Dosagem de Medicamento\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Descoberta de Drogas/métodos\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Ensaios Antitumorais Modelo de Xenoenxerto\t\t\t\t\t\t\t\t
  • Esquema de Medicação\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Humanos\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Inibidores de Proteínas Quinases/administração &am
  • Inibidores de Proteínas Quinases/farmacocinética\t\t
  • Linhagem Celular Tumoral\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Modelos Biológicos\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Neoplasias/enzimologia\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Neoplasias/patologia\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Neoplasias/quimioterapia\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Pesquisa Médica Translacional/métodos\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Pirazóis/administração & dosagem\t\t\t\t\t\t\t\t\t\t
  • Pirazóis/farmacocinética\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Piridinas/administração & dosagem\t\t\t\t\t\t\t\t\t
  • Piridinas/farmacocinética\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Proteínas Proto-Oncogênicas c-met/antagonistas &am
  • Proteínas Proto-Oncogênicas c-met/metabolismo\t\t\t\t\t
  • Receptores Proteína Tirosina Quinases/antagonistas
  • Receptores Proteína Tirosina Quinases/metabolismo\t
  • Relação Dose-Resposta a Droga\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t
  • Simulação por Computador\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t

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