Abstract 4665: Enhancing preclinical testing of agents in patient-derived pediatric solid tumor orthotopic xenografts with pharmacokinetics
Authors: Freeman Burgess B. , Blankenship Kaley , Dyer Michael A. , Stewart Elizabeth 
Published: April 2023

Abstract
Understanding a potential therapeutic agent’s in vivo pharmacokinetics (PK) is important in translating findings from preclinical murine efficacy models to patients. In consideration of this, PK evaluations play a prominent up-front role in our pediatric solid tumor testing pipeline. The aim of such PK studies is to define an agent’s PK under our experimental conditions – i.e. our mouse strain, husbandry, chow, source and lot of agent, and formulation. We ultimately relate our mouse plasma exposures to the known or anticipated exposures in humans or children, thereby deriving a clinically relevant dose (CRD). Preclinical testing of novel agents and combinations are performed simultaneously with the testing of standard of care agents using the CRD and schedule to allow for more unbiased assessment of efficacy. To date, our group has studied the PK of over 35 agents, predominantly investigational new drugs, in both normal and patient-derived orthotopically xenografted (PDOX) immuno-deficient mice. When possible, rhabdomyosarcoma and neuroblastoma PDOXs were destructively sampled over time to evaluate an agent’s intra-tumor exposure. All samples were quantified using sensitive, specific, and research- or qualified-tier LC-MS/MS assays. Roughly 70% of the agents had adequate tumor penetration, approaching or exceeding concentrations in the plasma. This was unsurprising, given that many test agents had reportedly high volume of distribution (Vd) values. While most of our mouse PK exposure parameters (e.g. Cmax, AUC) were in line with available previous reports, several agents varied appreciably, generally trending lower. We speculate that this may be due to differing study conditions, test agent physical forms, or formulations. CRD estimates were based upon unbound (when available) steady-state plasma AUC equivalencies between mice and humans for a defined clinical dosage regime. Some latitude was permitted in the recommended CRD, and being within two-fold of clinical target was generally considered acceptable. The resultant mouse CRDs and updated PK results for studied agents will be presented, with this information also being openly available upon request and/or at http://cstn.stjude.cloud. In conclusion, we have found that PK-driven, clinically relevant dosing enhances the efficiency and rigor in our in vivo efficacy testing program. Such an approach minimizes false positive signals arising from supra-clinically relevant doses and exposures in mouse models, allowing us to focus on efficacious agents and regimens for rapid clinical translation.
Citation Format: Burgess B. Freeman, Kaley Blankenship, Michael A. Dyer, Elizabeth Stewart. Enhancing preclinical testing of agents in patient-derived pediatric solid tumor orthotopic xenografts with pharmacokinetics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4665.