PhD Student Center of Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, United States
Objectives: Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) therapeutics have emerged as potent tools in gene therapy, targeting gene expression with high specificity. However, their delivery and distribution profiles pose significant challenges, influencing their clinical efficacy and safety. To address these challenges, we developed a comprehensive whole body physiologically based pharmacokinetic (PBPK) model incorporating both one-pore and two-pore mechanisms. This model aims to simulate the complex biodistribution of ASOs and siRNAs, accounting for tissue-specific uptake, cellular internalization, and clearance mechanisms across species.
Methods: Pharmacokinetic data of ASO and siRNA for multiple species (mouse, rat, NHP and human) were obtained from the literature for different case studies1, 2, 3, 4. The PBPK model incorporates the following mechanisms upon administration via different route (IV, IT and SC): 1) Internalization via clathrin mediated endocytosis; 2) Internalization via small and large pore through macropinocytosis, convection and diffusion; 3) A circular isogravimetric flow between large pores and small pores that is driven by the osmotic pressure; 4) Endonuclease and exonuclease mediated degradation; 5) For siRNA uptake via the ASGPR receptor was taken into consideration; 6) Linking drug specific attributes to molecular descriptors such as hydrodynamic radius and molecular weight.
Results: The one pore model was able to recapitulate the reported pharmacokinetics of ASO and siRNA. The rate of internalization for anterior brain in humans for ASO was estimated to be 836.612 1/h (17% RSE), The rate of internalization for posterior brain in humans for ASOs was estimated to be 0.203 1/h (30% RSE), The rate of internalization for rest of all tissues in humans for ASOs was estimated to be 0.0017 1/h (141% RSE). The rate of exocytosis in the anterior and posterior brain were also estimated to be 1.411 1/h (14.2% RSE) and 14834 1/h (142% RSE). Due to it’s complexity, the two pore model was simulated5, 6based on the estimates from the one-pore model, which resulted in acceptable %PE for the simulated two pore model.
Conclusion: The one-pore and two-pore models were able to adequately capture the reported PK for both ASO and siRNA. This modelling effort also helped derive the biodistribution coefficient for both the drugs after different route of administration as well as was able to link drug specific attributes with molecular weight and hydrodynamic radius.
Citations: 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)
