Article

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Authors: Qing-yu Yao1, Jian Li1,2, Rong Chen1, Ye Yao1, Jun-sheng Xue1, Wen-jun Chen1, Wei Lu1, Tian-yan Zhou1
1 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2 Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
Correspondence to: Qing-yu Yao: tianyanzhou@bjmu.edu.cn, Tian-yan Zhou: tianyanzhou@bjmu.edu.cn,
DOI: 10.1038/s41401-019-0251-7
Received: 20 March 2019
Accepted: 12 May 2019
Advance online: 5 June 2019

Abstract

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg−1·d−1) or SUL (25, 50 mg·kg−1·d−1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill’s function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.
Keywords: breast cancer; dexamethasone; sulpiride; pharmacokinetic/pharmacodynamic model; synergistic effect

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