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Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma

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Summary

Purpose. Emerging evidence suggests that 5' Adenosine Monophosphate-Activated Protein Kinase (AMPK), a key regulator of cellular bioenergetics, is a novel target for the treatment of glioblastoma (GBM), a lethal brain tumor. SBI-0206965, an aminopyrimidine derivative, is a potent AMPK inhibitor being investigated for the treatment of GBM. Here we characterized the systemic and brain pharmacokinetics (PK) and hepatic metabolism of SBI-0206965. Methods. We performed intracerebral microdialysis to determine brain partitioning of SBI-0206965 in jugular vein cannulated rats. We assessed systemic PK of SBI-0206965 in rats and C57BL/6 mice following oral administration. Employing human, mouse, and rat liver microsomes we characterized the metabolism of SBI-0206965. Results. SBI-0206965 is quickly absorbed, achieving plasma and brain extracellular fluid (ECF) peak levels within 0.25 – 0.65 h. Based on the ratio of Cmax and AUC in brain ECF to plasma (corrected for protein binding), brain partitioning is ~ 0.6—0.9 in rats. However, the compound has a short elimination half-life (1–2 h) and low relative oral bioavailability (~ 0.15). The estimated in-vitro hepatic intrinsic clearance of SBI-0206965 in mouse, rat and human was 325, 76 and 68 mL/min/kg, respectively. SBI-0206965 metabolites included desmethylated products, and the metabolism was strongly inhibited by ketoconazole, a CYP3A inhibitor. Conclusion. SBI-0206965 has adequate brain permeability but low relative oral bioavailability which may be due to rapid hepatic metabolism, likely catalyzed by CYP3A enzymes. Our observations will facilitate further development of SBI-0206965, and/or other structurally related molecules, for the treatment of GBM and other brain tumors.

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Data availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

University of Cincinnati Brain Tumor Center (Pankaj B. Desai) and National Institutes of Health (NIH) partially funded this project grants R01NS099162 and R01NS114074 (Biplab DasGupta).

Funding

This project was partially funded by University of Cincinnati Brain Tumor Center (Pankaj B. Desai) and National Institutes of Health (NIH) grants R01NS099162 and R01NS114074 (Biplab DasGupta).

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA

    Janki M. Desai, Aniruddha S. Karve, Gary A. Gudelsky & Pankaj B. Desai

  2. Division of Oncology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    William Seibel & Biplab DasGupta

  3. R. Marshall Wilson Mass Spectrometry Facility, Rieveschl Laboratories for Mass Spectrometry, Department of Chemistry, College of Arts and Sciences, University of Cincinnati, Cincinnati, OH, USA

    Larry Sallans

  4. Center for Immunotherapy and Precision Immuno-Oncology (CITI), Lerner Research Institute - Cleveland Clinic, Cleveland, OH, USA

    Mruniya V. Gawali

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  1. Janki M. Desai
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Contributions

All authors contributed to the study conception, design, material preparation, data collection and analysis. The first draft of the manuscript was written by Janki M. Desai and Pankaj B. Desai and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Pankaj B. Desai.

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The experimental protocol for rat study was approved by the University of Cincinnati Institutional Animal Care and Use Committee (IACUC, Protocol No. 20–01-24–01). C57BL/6 mice were generated by in-house breeding at the Cincinnati Children’s Hospital Medical Center (CCHMC; Cincinnati, OH). Housing and experimental protocols employing C57BL/6 mice were approved by the CCHMC IACUC (Protocol No. IACUC2021-0031).

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The authors have no relevant financial or non-financial interests to disclose.

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Desai, J.M., Karve, A.S., Gudelsky, G.A. et al. Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma. Invest New Drugs 40, 944–952 (2022). https://doi.org/10.1007/s10637-022-01278-8

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