(T-006) Translational two-pore PBPK model to characterize whole-body disposition of different-size oligonucleotide therapeutics
Tuesday, October 21, 2025
7:00 AM - 1:45 PM MDT
Location: Colorado A
Devam Desai, MS – Center of Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL; Rodrigo Cristofoletti – Center of Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL
PhD Student Center of Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, United States
Disclosure(s):
Devam A. Desai, M.S.: No financial relationships to disclose
Objectives: The pharmacokinetics (PK) of oligonucleotide therapeutics are governed by complex processes such as size-dependent tissue extravasation, renal clearance, and intracellular trafficking. While existing physiologically based pharmacokinetic (PBPK) models have advanced our understanding of oligonucleotide disposition, most are limited in either molecular diversity, scope of biological mechanisms, or interspecies translation. To address these limitations, we aimed to develop and optimize a mechanistic, translational two-pore PBPK model that accounts for molecular weight (MW)-dependent distribution and clearance pathways for oligonucleotides, enabling prediction of systemic and tissue exposures across preclinical species and humans.
Methods: A whole-body PBPK model incorporating two-pore formalism was constructed and parameterized to describe both convective and diffusive transport across vascular endothelium based on oligonucleotide size and physicochemical properties. The model includes size-dependent renal clearance, endosomal recycling where applicable (e.g., for GalNAc-conjugated oligonucleotides), and lysosomal degradation. A diverse dataset—including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), was curated across four species: mice, rats, monkeys, and humans. Tissue-specific physiological parameters were adapted for each species, and model calibration was performed using plasma and tissue PK profiles with literature-sourced data1,2,3,4.
Results: The developed PBPK model accurately recapitulates the plasma and tissue disposition of oligonucleotides ranging in molecular weight from ~6 to 20 kDa. Predicted area under the curve (AUC) values for most oligonucleotides were within a two-fold error compared to observed data5,6. The model captured key features of oligonucleotide pharmacokinetics, including rapid systemic clearance for smaller, unmodified species, and prolonged circulation for larger or conjugated molecules. Sensitivity analyses identified molecular weight, charge, and chemical modification as primary drivers of extravasation and clearance. The model also quantitatively characterized contributions of filtration, lysosomal degradation, endonucleases metabolism, and endosomal recycling to overall elimination.
Conclusions: We present a cross-species, cross-modality PBPK model that enables quantitative prediction of oligonucleotide pharmacokinetics across a range molecular size. By incorporating mechanistic insights into size-dependent transport and clearance, the model provides a platform to support rational design, species translation, and dose selection for oligonucleotide therapeutics. This framework lays the foundation for integrating additional complexities such as characterization of different structural asymmetries, and intracellular pharmacodynamics in future iterations.
Citations: References 1. Ayyar VS, Song D. Mechanistic Pharmacokinetics and Pharmacodynamics of GalNAc-siRNA: Translational Model Involving Competitive Receptor-Mediated Disposition and RISC-Dependent Gene Silencing Applied to Givosiran. Journal of Pharmaceutical Sciences 113 176-190. (2024)
2. Ayyar VS, Song D, Zheng S, Carpenter T, Heald DL. Minimal Physiologically Based Pharmacokinetic-Pharmacodynamic (mPBPK-PD) Model of N-Acetylgalactosamine-Conjugated Small Interfering RNA Disposition and Gene Silencing in Preclinical Species and Humans. J Pharmacol Exp Ther 379 134-146. (2021)
3. Mazur C, et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight 4. (2019)
4. Yamamoto Y, et al. Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma. CPT Pharmacometrics Syst Pharmacol 12 1213-1226. (2023)
5. Li Z, Li Y, Chang HP, Yu X, Shah DK. Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice. J Pharmacokinet Pharmacodyn 48 743-762. (2021)
6. Li Z, Shah DK. Two-pore physiologically based pharmacokinetic model with de novo derived parameters for predicting plasma PK of different size protein therapeutics. J Pharmacokinet Pharmacodyn 46 305-318. (2019)
