Semi-Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for the Combination Use of Dexamethasone and Gemcitabine in Breast Cancer.
Our study aimed at the investigation of in vivo anticancer effect of the combination use of dexamethasone (DEX) and gemcitabine (GM) as well as the development of pharmacokinetic/pharmacodynamic (PK/PD) models in MCF-7 xenograft model. Further, simulations were conducted to optimize doses and administration schedules. The inhibitory effect of different doses and administration schedules were investigated in MCF-7 xenograft model. Semi-mechanism-based PK/PD models were established based on the preclinical data to characterize the relationship between plasma concentration and the time course of the drug response quantitatively. The PK/PD models were further applied to predict and optimize doses and administration schedules, which would lead to tumor stasis by the end of the treatment. Synergistic effect was observed in the PD study in vivo and further confirmed by the estimated combination index ψ obtained from PK/PD models. The optimum dose regimen was selected as DEX 2 mg/kg, qd and GM 10 mg/kg, q2d based on the simulation results. In summary, the PD interaction between DEX and GM was demonstrated as synergism by both experimental results and modeling approach. Dosage regimens were optimized as predicted by modeling and simulations, which would provide reference for preclinical study and translational research as well.
School of Pharmaceutical Science, Peking University, Beijing 100191, China.
Yin
Y
Yuan
School of Pharmaceutical Science, Peking University, Beijing 100191, China.
Xuan
X
Zhou
School of Pharmaceutical Science, Peking University, Beijing 100191, China.
Yupeng
Y
Ren
The Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing 100191, China.
Shupei
S
Zhou
School of Pharmaceutical Science, Peking University, Beijing 100191, China.
Lijie
L
Wang
School of Pharmaceutical Science, Peking University, Beijing 100191, China.
Shuangmin
S
Ji
The Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing 100191, China.
Ming
M
Hua
School of Pharmaceutical Science, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Liang
L
Li
School of Pharmaceutical Science, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Wei
W
Lu
School of Pharmaceutical Science, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: tianyanzhou@bjmu.edu.cn.
Tianyan
T
Zhou
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D003907:Dexamethasone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D003907:Dexamethasone; D000093542:Gemcitabine
cancer chemotherapy; drug interaction; in silico modeling; pharmacokinetic/pharmacodynamic models; simulation