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Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of
Jun Wang1, Ting Chen1, Donna M Ruszaj1
1Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
Abstract:
Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of monoclonal antibodies (mAb). A linked pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to integrate the plasma and tumor PK of a sHHi priming agent with its effects upon downstream stromal biomarkers Gli1, hyaluronic acid, and interstitial fluid pressure in PDAC patient-derived xenograft (PDX) tumors. In parallel, in situ tumor concentrations of cetuximab (CTX: anti-epidermal growth factor receptor; EGFR) were quantified as a marker for tumor delivery of mAb or antibody-drug conjugates. A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve.
Insights
Pancreatic cancer treatments fail due to poor drug delivery. Hedgehog pathway inhibitors enhance tumor permeability, improving antibody delivery and efficacy. This study models this effect to optimize antibody dosing strategies for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- Therapeutic antibodies show limited efficacy against pancreatic ductal adenocarcinomas (PDAC) due to tumor barriers like desmoplasia and poor perfusion.
- Insufficient drug penetration into tumors hinders effective treatment, leading to therapeutic failure.
Purpose of the Study:
- To investigate how temporal dynamics of tumor priming impact intratumor distribution of monoclonal antibodies (mAbs).
- To develop a quantitative, mechanistic understanding of enhancing drug delivery in PDAC.
- To identify optimal dosing regimens for therapeutic antibodies in PDAC.
Main Methods:
- Developed a linked pharmacokinetic (PK)/pharmacodynamic (PD) model for a smoothened inhibitor of hedgehog signaling (sHHi) priming agent.
- Integrated sHHi's effects on stromal biomarkers (Gli1, hyaluronic acid, interstitial fluid pressure) in PDAC patient-derived xenograft (PDX) tumors.
- Quantified in situ cetuximab (CTX) concentrations and EGFR occupancy using a minimal physiologically-based pharmacokinetic (mPBPK) model.
Main Results:
- Smoothened inhibitors of hedgehog signaling (sHHi) were shown to increase PDAC tumor permeability, perfusion, and drug delivery.
- The integrated mPBPK and PK/PD models identified critical physiological parameters for antibody distribution.
- The models provide insights into dosing strategies for maximal therapeutic antibody disposition during transient tumor permeability compromise.
Conclusions:
- Tumor priming strategies can transiently enhance PDAC permeability, improving antibody delivery.
- Mechanistic modeling is crucial for understanding and optimizing antibody pharmacokinetics in PDAC.
- This approach offers a pathway to improve therapeutic antibody efficacy in pancreatic cancer.
