TY - JOUR T1 - <strong>Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000730 SP - JPET-AR-2021-000730 AU - Kristen M Van Eaton AU - Daniel L Gustafson Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/09/09/jpet.121.000730.abstract N2 - Hydroxychloroquine (HCQ) is being tested in a number of human clinical trials to determine the role of autophagy in response to standard anticancer therapies. However, HCQ pharmacodynamic responses are difficult to assess in patients and preclinical studies in mouse models are equivocal with regard to HCQ exposure and inhibition of autophagy. Here, pharmacokinetic (PK) assessment of HCQ in non-tumor bearing mice following intraperitoneal (IP) dosing established 60 mg/kg as the human equivalent dose of HCQ in mice. Autophagy inhibition, cell proliferation, and cell death were assessed in 2D cell culture and 3D tumor organoids in breast cancer. Mice challenged with breast cancer xenografts were then treated with 60 mg/kg HCQ via IP dosing and subsequent PK and pharmacodynamic (PD) responses were assessed. Although autophagic flux was significantly inhibited in cells irrespective of autophagy dependency status, autophagy dependent tumors had decreased cell proliferation and increased cell death at earlier time points compared to autophagy independent tumors. Overall, this study shows that 2D cell culture, 3D tumor organoids, and in vivo studies produce similar results and in vitro studies can be used as surrogates to recapitulate in vivo antitumor responses of HCQ. Significance Statement Autophagy dependent tumors, but not autophagy independent tumors, have decreased cell proliferation and increased cell death following single agent hydroxychloroquine treatment. However, hydroxychloroquine causes decreased autophagic flux regardless of autophagy status, suggesting its clinical efficacy in the context of autophagy inhibition. ER -