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Preclinical Pharmacokinetic/Pharmacodynamic Models to Predict Schedule-Dependent Interaction Between Erlotinib and Gemcitabine

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Abstract

Purpose

To investigate the pharmacological effects of different erlotinib (ER) and gemcitabine (GM) combination schedules by in vitro and in vivo experiments and PK/PD models in non-small cell lung cancer cells.

Methods

H1299 cells were exposed to different ER combined with GM schedules. Cell growth inhibition was analyzed to evaluate these schedules. A preclinical in vivo study was then conducted to compare tumor suppression effects of different schedules in H1299 xenografts. PK/PD models were developed to quantify the anti-tumor interaction of ER and GM.

Results

Synergism was observed when ER preceded GM, but other sequences showed antagonism. The optimal in vitro schedule, or interval schedule, was applied to the animal study, which showed greater anti-tumor effect than simultaneous group. PK/PD models implied that interaction of the two drugs was additive in simultaneous treatment but synergistic in interval schedule. The simulation results showed that interval schedule can delay tumor growth for a longer time, and demonstrated more evident anti-tumor effect compared with simultaneous group if the treatment duration was longer.

Conclusions

Interval schedule of the two drugs can achieve synergistic anti-tumor effect, and is superior to simultaneous treatment.

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Abbreviations

EGFR:

epidermal growth factor receptor

ER:

erlotinib

FDA:

Food and Drug Administration

FOCE:

first order conditional estimation

GM:

gemcitabine

MTD:

maximum tolerated dose

NSCLC:

non-small-cell lung cancer

OD:

optical density

PBS:

phosphate buffered saline

PK/PD:

pharmacokinetic/pharmacodynamic

SRB:

sulforhodamine B

TKI:

tyrosine kinase inhibitor

VPC:

visual predictive check

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Acknowledgments and Disclosures

This work was supported by the Ministry of Science and Technology of the People’s Republic of China Grant 2009ZX09301-010 and National Natural Science Foundation of China (NSFC) Grant 81273583.

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Liang Li, Tianyan Zhou & Wei Lu

  2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Mengyao Li, Hanqing Li, Xiaoliang Cheng, Xipei Wang, Liang Li, Tianyan Zhou & Wei Lu

Authors
  1. Mengyao Li
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  2. Hanqing Li
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  3. Xiaoliang Cheng
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  5. Liang Li
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  7. Wei Lu
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Correspondence to Tianyan Zhou or Wei Lu.

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Li, M., Li, H., Cheng, X. et al. Preclinical Pharmacokinetic/Pharmacodynamic Models to Predict Schedule-Dependent Interaction Between Erlotinib and Gemcitabine. Pharm Res 30, 1400–1408 (2013). https://doi.org/10.1007/s11095-013-0978-7

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  • DOI: https://doi.org/10.1007/s11095-013-0978-7

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