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Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

CSC:

Cancer stem cell

DA:

Dopamine

FOCE:

First order conditional estimation

NSCLC:

Non-small-cell lung cancer

PDGFR:

Platelet-derived growth factor receptor

PK/PD:

Pharmacokinetic/pharmacodynamics

SUN:

Sunitinib

VEGFR:

Vascular endothelial growth factor receptor

VPC:

Visual predictive check

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by the National Natural Science Foundation of China. (Grant No. 81473277). The first author of this article was sponsored by the Department of Pharmacometrics of Pfizer.

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Authors and Affiliations

  1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Fangran Hao, Siyuan Wang, Xiao Zhu, Junsheng Xue, Jingyun Li, Lijie Wang, Jian Li, Wei Lu & Tianyan Zhou

  2. State Key Laboratory of Nature and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Wei Lu & Tianyan Zhou

Authors
  1. Fangran Hao
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  2. Siyuan Wang
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  3. Xiao Zhu
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  4. Junsheng Xue
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Correspondence to Tianyan Zhou.

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Hao, F., Wang, S., Zhu, X. et al. Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft. Pharm Res 34, 408–418 (2017). https://doi.org/10.1007/s11095-016-2071-5

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  • DOI: https://doi.org/10.1007/s11095-016-2071-5

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