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Dose-dependent bioavailability, absorption-rate limited elimination, and tissue distribution of the ATR inhibitor BAY-1895344 (elimusertib) in mice

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Abstract

Purpose

Ataxia Telangiectasia and Rad3-related (ATR) is a pivotal component of the DNA damage response and repair pathways that is activated in responses to cytotoxic cancer treatments. Several ATR inhibitors (ATRi) are in development that block the ATR mediated DNA repair and enhance the damage associated with cytotoxic therapy. BAY-1895344 (elimusertib) is an orally available ATRi with preclinical efficacy that is in clinical development. Little is known about the pharmacokinetics (PK) which is of interest, because tissue exposure and ATR inhibition may relate to toxicities or responses.

Methods

To evaluate BAY-1895344 PK, a sensitive LC–MS/MS method was utilized for quantitation in mouse plasma and tissues. PK studies in mice were first conducted to determine dose linearity. In vivo metabolites were identified and analyzed semi-quantitatively. A compartmental PK model was developed to describe PK behavior. An extensive PK study was then conducted in tumor-bearing mice to quantitate tissue distribution for relevant tissues.

Results

Dose linearity was observed from 1 to 10 mg/kg PO, while at 40 mg/kg PO bioavailability increased approximately fourfold due to saturation of first-pass metabolism, as suggested by metabolite analyses and a developed compartmental model. Longer half-lives in PO treated mice compared to IV treated mice indicated absorption-rate limited elimination. Tissue distribution varied but showed extensive distribution to bone marrow, brain, and spinal cord.

Conclusions

Complex PK behavior was limited to absorption processes which may not be recapitulated clinically. Tissue partition coefficients may be used to contrast ATR inhibitors with respect to their efficacy and toxicity.

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Abbreviations

ATR:

Ataxia telangiectasia and Rad3-related

ATRi:

Ataxia telangiectasia and Rad3-related inhibitor

XRT:

Radiation therapy

IR:

Ionizing radiation

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

PK:

Pharmacokinetics

NCA:

Noncompartmental analysis

IS:

Internal standard

MRM:

Multiple-reaction monitoring

TIC:

Total ion chromatogram

IV:

Intravenous

PO:

Oral

AUC:

Area under the curve

C max :

Maximum plasma concentration

T max :

Time of maximum plasma concentration

F:

Bioavailability

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Acknowledgements

This work was supported in-part by the National Institutes of Health grants TL1TR001858, R50CA211241, R01CA236367, and P30CA047904. This project used the UPMC Hillman Cancer Center, Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF). BFK was also supported in-part by a fellowship from the American Foundation for Pharmaceutical Education. This project is funded, in part, under a Grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.

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Authors and Affiliations

  1. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA

    Brian F. Kiesel, Joshua J. Deppas, Jianxia Guo, Robert. A. Parise & Jan H. Beumer

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Brian F. Kiesel, Joshua J. Deppas & Jan H. Beumer

  3. Department of Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    David A. Clump & Christopher J. Bakkenist

  4. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Christopher J. Bakkenist

  5. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jan H. Beumer

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  1. Brian F. Kiesel
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Correspondence to Jan H. Beumer.

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Kiesel, B.F., Deppas, J.J., Guo, J. et al. Dose-dependent bioavailability, absorption-rate limited elimination, and tissue distribution of the ATR inhibitor BAY-1895344 (elimusertib) in mice. Cancer Chemother Pharmacol 89, 795–807 (2022). https://doi.org/10.1007/s00280-022-04436-0

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