Pharmacokinetic Modeling of Oral siRNA Therapeutics for Treatment of Inflammatory Bowel Disease



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This thesis investigates the pharmacokinetics of orally administered small interfering RNA (siRNA) for the treatment of Inflammatory Bowel Disease (IBD). This study involves the construction of two physiologically based pharmacokinetic (PBPK) models to examine the absorption, distribution, metabolism, and elimination of siRNA across several physiological compartments in the gastrointestinal (GI) tract and within cells.

The first model, the GI transfer PBPK model, examines the pharmacokinetics of siRNA in eight compartments, from the stomach to the kidneys. Key parameters were derived from literature and data fitting in MATLAB SimBiology. Sensitivity analyses identified key rate constants that significantly influence siRNA concentrations, suggesting critical factors for optimizing IBD treatment. The second model, the cell PBPK model, examines the intracellular journey of siRNA within target cells in the ileum, focusing on endosomal uptake, cytoplasmic release, and binding to the RISC complex. Sensitivity analyses on this model indicated that endosomal escape and the association to RISC significantly impact siRNA's gene-silencing potential, suggesting critical points for optimizing therapeutic strategies at the cellular level.

The findings from these models contribute valuable insights into the pharmacokinetics of siRNA, guiding future research and optimization strategies for siRNA treatment of IBD.


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