In vitro to clinical translation of combinatorial effects of doxorubicin and dexrazoxane in breast cancer: a mechanism-based pharmacokinetic/pharmacodynamic modeling approach

Frontiers in Pharmacology

Pharmacology

Hardik Mody¹  Jovin Lezeau¹  Kareem Taha¹  Tanaya R. Vaidya¹  Sihem Ait-Oudhia² 

[1] Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, United States;Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc., Rahway, NJ, United States;

关键词: doxorubicin;    dexrazoxane;    breast cancer;    pharmacodynamic drug-drug interaction;    proof-of-concept study;   

DOI  :  10.3389/fphar.2023.1239141

 received in 2023-06-12, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not extensively studied. In this manuscript, a proof-of-concept in vitro study is carried out to quantitatively characterize the anticancer effects of DOX and DEX and determine their nature of drug-drug interactions in cancer cells by combining experimental data with modeling approaches. First, we determined the static concentration-response of DOX and DEX in breast cancer cell lines, JIMT-1 and MDA-MB-468. With a three-dimensional (3D) response surface analysis using a competitive interaction model, we characterized their interaction to be modestly synergistic in MDA-MB-468 or modestly antagonistic in JIMT-1 cells. Second, a cellular-level, pharmacodynamic (PD) model was developed to capture the time-course effects of the two drugs which determined additive and antagonistic interactions for DOX and DEX in MDA-MB-468 and JIMT-1, respectively. Finally, we performed in vitro to in vivo translation by utilizing DOX and DEX clinical dosing regimen that was previously identified to be maximally cardioprotective, to drive tumor cell PD models. The resulting simulations showed that a 10:1 DEX:DOX dose ratio over three cycles of Q3W regimen of DOX results in comparable efficacy based on MDA-MB-468 (additive effect) estimates and lower efficacy based on JIMT-1 (antagonistic effect) estimates for DOX + DEX combination as compared to DOX alone. Thus, our developed cell-based PD models can be used to simulate different scenarios and better design preclinical in vivo studies to further optimize DOX and DEX combinations.

【 授权许可】

Unknown   
Copyright © 2023 Mody, Vaidya, Lezeau, Taha and Ait-Oudhia.