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Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice

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Abstract

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity. SHetA2 concentrations in plasma and 14 different tissues were measured at various time points after a single intravenous dose of 10 mg/kg and oral dose of 60 mg/kg, and these data were used to develop a whole-body PBPK model. SHetA2 exhibited a multi-exponential plasma concentration decline with an elimination half-life of 4.5 h. Rapid and extensive tissue distribution, which was best described by a perfusion rate–limited model, was observed with the tissue-to-plasma partition coefficients (kp = 1.4–21.2). The PBPK modeling estimated the systemic clearance (76.4 mL/h) from circulation as a main elimination pathway of SHetA2. It also indicated that the amount absorbed into intestine was the major determining factor for the oral bioavailability (22.3%), while the first-pass loss from liver and intestine contributed minimally (< 1%). Our results provide an insight into SHetA2 tissue distribution characteristics. The developed PBPK model can be used to predict the drug exposure at tumors or local sites of action for different dosing regimens and scaled up to humans to correlate with efficacy.

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Acknowledgments

We are thankful to Dr. Anil Sood, MD Anderson Cancer Center, for providing the SKOV3-luc cells.

Funding

This work was made possible in part by the College of Pharmacy, Stephenson Cancer Center Gynecologic Cancer Program, and NIH R01s (1R01CA196200 and 1R01CA200126).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Ankur Sharma, Mengjie Li, Mariam Ibrahim, Lucila Garcia-Contreras & Sukyung Woo

  2. Department of Obstetrics and Gynecology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Elangovan Thavathiru & Doris M Benbrook

  3. Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Doris M Benbrook & Sukyung Woo

Authors
  1. Ankur Sharma
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  2. Mengjie Li
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  5. Lucila Garcia-Contreras
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Contributions

Participated in research design: Sharma, Woo, and Benbrook

Conducted experiments: Sharma, Thavathiru, Ibrahim, Woo, and Benbrook

Contributed new reagents or analytical tools: Sharma, Woo, and Benbrook

Performed data analysis: Sharma, Li, and Woo

Wrote or contributed to the writing of the manuscript: Sharma, Li, Ibrahim, and Woo

Reviewed and edited the writing of the manuscript: Sharma, Li, Thavathiru, Ibrahim, Garcia-Contreras, Woo, and Benbrook

Corresponding author

Correspondence to Sukyung Woo.

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Sharma, A., Li, M., Thavathiru, E. et al. Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice. AAPS J 22, 51 (2020). https://doi.org/10.1208/s12248-020-0421-z

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