title: Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.
abstract: OBJECTIVE
  Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen.
  
  
  METHODS
  ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen.
  
  
  RESULTS
  The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research.
  
  
  CONCLUSIONS
  The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jing-Yun
authors.initials: JY
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Shuang-Min
authors.initials: SM
authors.lastname: Ji
authors.affiliation: Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing 100191, China.
authors.forename: Shu-Pei
authors.initials: SP
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Mou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Tian-Yan
authors.initials: TY
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D011758:Pyrroles; D000069347:Erlotinib Hydrochloride; D000077210:Sunitinib