Systemic And Cns Distributional Pharmacokinetics Of Novel Dna Damage Response Inhibitors: Implications For The Treatment Of Brain Tumors

Abstract

CNS tumors are among the leading causes of death across all age groups and present a critical unmet need. Despite advancements in CNS tumor diagnostics and use of molecular profiling in tumor classification that have improved our understanding of tumor pathophysiology, there has been limited clinical success in the treatment of brain tumors. This can be attributed in part to the anatomical location of the tumor and challenges associated with brain drug delivery. Numerous failed clinical trials where dose selection was based primarily on observed drug efficacy have highlighted the importance of evaluating exposure-response-effect relationships to inform decisions about dosing regimens. The current standard of care for brain tumors includes surgery, radiation, and chemotherapy. Subsequent activation of DNA damage response pathways induces resistance to DNA damaging radiation and chemotherapy. Therefore, DNA damage response inhibitors are being explored as radio- and chemo-sensitizers to increase the efficacy of DNA damaging radiation and chemotherapy. WSD0628, an ATM inhibitor, and elimusertib, an ATR inhibitor, inhibit the key regulators of the DNA damage response. We evaluated the preclinical systemic pharmacokinetics and CNS distribution of these drugs for evaluating their potential in the treatment of brain tumors. Mechanisms influencing the exposure of pharmacologically active drug in the tissues of interest, such as role of efflux transporters, drug binding to plasma and CNS tissues were evaluated along with in vitro potency and in vivo efficacy in orthotopic tumor bearing mouse models. We used modeling and simulation approaches to predict exposures in tissues of interest and correlate with in vivo efficacy. We observed a greater-than-dose-proportional increase in exposure of WSD0628 in plasma and brain, potentially due to the saturation of the clearance pathways. WSD0628 is homogenously distributed throughout all brain regions and CNS distribution of WSD0628 is not limited by P-gp or Bcrp. Based on our observations, WSD0628 is a potent radiosensitizer with adequate CNS distribution for efficacy in primary and secondary brain tumors and has potential for further exploration. The nonlinear pharmacokinetic behavior of WSD0628 was modeled by simultaneous fitting of the observed concentration time profiles and we propose a model framework for establishing the exposure-response-effect relationship of WSD0628 for the treatment of brain tumors. We also evaluated the potential reasons for lack of preclinical in vivo efficacy of elimusertib in combination with the current standard of care therapies for brain tumors. We observed that the CNS distribution of elimusertib was limited due to rapid clearance from systemic circulation, high extent of binding to CNS tissues, and to a lower extent P-gp mediated active efflux. This resulted in no change in in vivo efficacy in combination with radiation and temozolomide in orthotopic GBM PDX mouse models despite an observed robust in vitro synergy with temozolomide. Acknowledging the potential for species differences, our results indicate that elimusertib may have limited potential for treatment of brain tumors. Taken together, these observations provide critical insights into the potential of these drugs for the treatment of brain tumors and will enable informed decisions in the development of these molecules.