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Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing
Ankur Sharma1, Mengjie Li1, Elangovan Thavathiru2
1Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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.
Insights
The novel anticancer drug SHetA2 distributes widely in tissues, with absorption in the intestine being key to its oral bioavailability. A PBPK model aids in predicting drug exposure for optimized cancer treatment.
Area of Science:
- Pharmacology
- Oncology
- Drug Development
Background:
- SHetA2 is an orally available small molecule targeting cancer cells.
- It is under clinical development for cancer treatment and prevention.
- Understanding its tissue distribution is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To characterize the tissue distribution of SHetA2 in tumor-bearing mice.
- To develop a physiologically based pharmacokinetic (PBPK) model for SHetA2.
- To investigate factors influencing SHetA2's oral bioavailability.
Main Methods:
- An orthotopic SKOV3 ovarian cancer xenograft mouse model was utilized.
- SHetA2 concentrations were measured in plasma and 14 tissues post-IV and oral administration.
- A whole-body PBPK model was developed using the collected pharmacokinetic data.
Main Results:
- SHetA2 showed rapid and extensive tissue distribution, best modeled as perfusion rate-limited.
- The elimination half-life was 4.5 hours, with systemic clearance estimated at 76.4 mL/h.
- Oral bioavailability was 22.3%, primarily determined by intestinal absorption, with minimal first-pass loss.
Conclusions:
- The PBPK model provides insights into SHetA2's tissue distribution and elimination pathways.
- The model can predict drug exposure at target sites for various dosing regimens.
- This PBPK model can be scaled to humans to correlate drug exposure with efficacy.
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