title: Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft.
abstract: To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens.
  
  
  
  A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens.
  
  
  
  The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study.
  
  
  
  The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Fangran
authors.initials: F
authors.lastname: Hao
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Xue
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China.|State Key Laboratory of Nature and Biomimetic Drugs, Peking University, Beijing, 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China. tianyanzhou@bjmu.edu.cn.|State Key Laboratory of Nature and Biomimetic Drugs, Peking University, Beijing, 100191, China. tianyanzhou@bjmu.edu.cn.
authors.forename: Tianyan
authors.identifier: 0000-0003-2583-8080
authors.initials: T
authors.lastname: Zhou
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004298:Dopamine / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib; D004298:Dopamine
keywords: PK/PD model; combination therapy; dopamine; on/off effect; sunitinib