Fangran Hao, Siyuan Wang, Wei Lu, Tianyan Zhou
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China
Objectives: Lung cancer is the most lethal form of cancer in the world (1). Sunitinib is a promising multi-targeted receptor tyrosine kinase (RTK) inhibitor with activity against vascular endothelial growth factor receptors (VEGFR-1 and -2), platelet-derived growth factor receptors (PDGFR-α and -β), stem-cell factor receptor (KIT), etc (2). However, drug resistance (3) has limited its clinical application. In order to investigate the possibility of reversion of multidrug resistance in lung adenocarcinoma cell line A549, the study attempted to explore the anti-tumor synergistic effect of dopamine on sunitinib in a human non-small lung cancer xenograft, as well as to develop the PK/PD models of this combination therapy.
Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line A549. In the monotherapy group, the animals were given sunitinib (10 or 20mg/kg) by oral administration daily or two different doses of dopamine (1 or 2mg/kg) by tail intravenous injection every three days; in the combination therapy group, 10mg/kg sunitinib was given concurrently with 1mg/kg dopamine and 20mg/kg sunitinib was given concurrently with 2mg/kg dopamine. Pharmacokinetics of sunitinib was determined in our previous study (4). The natural growth curves of A549 cells xenografts could be well fitted with an exponential phase followed by a linear growth phase. A transit compartment model was introduced to describe the cell-killing effect induced by sunitinib. The influence of dopamine on the model was reflected via an on/off effect.
Results: The pharmacokinetics of sunitinib and its active metabolite SU12662 was described by a two-compartment model with first-order extravascular absorption kinetics. Evident synergism was observed when sunitinib and dopamine were given concurrently, as the combination therapy exhibited remarkable lower tumor burden than the monotherapy. A shape factor was put on the apoptosis rate constant to explain the enhanced antitumor effects, which was estimated as 0.003. The transit rate constant obtained from the model was estimated as 0.519 and the first order apoptosis rate constant was 0.126. The good predictive function was found by visual predictive check.
Conclusion: The pharmacokinetic/pharmacodynamics model built in this study contributes to understanding the synergistic effect of dopamine on sunitinib. Furthermore, it is helpful in predicting the efficacy of dopamine when combined with other chemotherapeutic drugs.
References:
References:
[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
[2] Li M, Li H, Cheng X, Wang X, Li L, Zhou T, et al. Preclinical pharmacokinetic/pharmacodynamic models to predict schedule-dependent interaction between erlotinib and gemcitabine. Pharm Res. 2013;30(5):1400-8.
[3] Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A. 2012;109:2784-9.
[4] Jingyu L, Tianyan Z. Simultaneous determination of sunitinib and its active metabolites N-desethylsunitinib (SU12662) in nude mice plasma by liquid chromatography tandem mass spectrometry and its application to a pharmacokinetic study. J Chin pharm Sci. 2015;24(4).
Reference: PAGE 25 (2016) Abstr 5989 [www.page-meeting.org/?abstract=5989]
Poster: Drug/Disease modeling - Oncology