Kiesel, Brian Forrest
(2022)
The Pharmacokinetics, Toxicity, and Immunological Effects of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitors AZD6738 (ceralasertib) and BAY-1895344 (elimusertib).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Despite improvements in cancer diagnosis and treatment there were still approximately 1.9 million diagnosed cases and 600,000 deaths among Americans in 2021. Common treatment modalities for cancer are ionizing radiation (IR) and chemotherapy, which mostly accomplish their effects by causing DNA damage in cancer cells. Current research has identified several key pathways in cancer cells that are activated in response to these treatments that limit DNA damage and are collectively referred to as the DNA damage response (DDR). The DDR ultimately can reduce the damage to cancer cells, allowing them to recover and mitigate the beneficial effects of anticancer treatments. A pivotal member of the DDR is the protein Ataxia-telangiectasia mutated and Rad3-related (ATR), an apical kinase responsible for recognizing and enacting responses to several forms of DNA damage and has been found to limit the effects of DNA damaging cancer treatments.
Several small molecule ATR inhibitors (ATRi) have been developed that limit the recovery of cancer cells to a DNA damaging treatment and several ATRi are in clinical development, including the oral ATRi AZD6738 (ceralasertib) and BAY-1895344 (elimusertib). While both ATRi have substantial preclinical evidence establishing efficacy, their ultimate clinical utility is unknown. Relevant questions still remain including if they exacerbate off-target damage to healthy tissues caused by DNA damaging agents. Differences in pharmacokinetics (PK) and tissue distribution among ATRi may produce non-overlapping toxicity profiles that may ultimately impact ATRi class member choice. Additionally, novel research has identified that AZD6738 enhances anti-tumor immune responses when administered with IR, but it is unknown if this effect extends to other ATRi and if dose or exposure are impactful to the effect.
Pharmacokinetic differences among AZD6738 and BAY-1895344 may provide empirical evidence to support differences in toxicity or immunological responses but information regarding their PK, including their bioavailability and dose linearity, is limited.
Using preclinical mouse models, the dose linearity and bioavailability of AZD6738 and BAY-1895344 were first established, followed by extensive tissue distribution studies to thoroughly determine tissue partition coefficients. In order to accomplish this, highly sensitive quantitative assays for both ATRi were developed according to FDA guidance for bioanalytical method validation. Separately, ATRi were administered with and without IR to establish and compare toxicity across readouts of gross pathology, blood counts, and histopathology. Lastly, studies were conducted to determine and compare the immunological effects of ATRi at various doses when administered with conformal IR using an established experimental model.
Both ATRi exhibited dose-dependent bioavailability, resulting in non-linear PK due to pre-systemic saturation of first-pass effects. Tissue distribution was similar for most tissues with notable exceptions, including a higher capacity for BAY-1895344 to penetrate the blood-brain barrier compared to AZD6738. Studies of toxicity largely demonstrated that neither ATRi acutely exacerbated measured toxicity when combined with IR although ATRi presented unique differences in toxicity when administered alone, including a unique observation of cardiotoxicity from AZD6738. Immunology experiments revealed that increases in the composition of antigen specific CD8+ T cells occurs for both ATRi indicating it may be a class effect.
The results reported in this body of work identify several commonalities between AZD6738 and BAY-1895344 for PK, toxicity, and immunology but also several unique properties which may impact their clinical utility. As both ATRi continue to progress through clinical development, the results reported here can guide clinical trial design and inform investigators of similarities and differences between them, which will hopefully result in safer more efficacious treatment options for cancer patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
21 March 2022 |
| Date Type: |
Publication |
| Defense Date: |
25 February 2022 |
| Approval Date: |
21 March 2022 |
| Submission Date: |
21 March 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
256 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pharmacology, pharmacokinetics, immunology, toxicity, DNA damage response, cancer treatment |
| Date Deposited: |
21 Mar 2022 13:12 |
| Last Modified: |
21 Mar 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42387 |
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