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Updated: Jan 18, 2026
Models and Methods to Evaluate Transport of Drug Delivery Systems Across Cellular Barriers
Published on: October 17, 2013
Modeling and Simulation Identifies Endocytosis Uptake Rate and Fraction Unbound as Important Predictors of
Felix Stader1, Abdallah Derbalah1, Adriana Zyla1
1Certara UK Ltd., Level 2 Acero, 1 Concourse Way, Sheffield, UK.
Abstract:
Therapeutic oligonucleotides (TOs) represent an emerging modality, which offers a promising alternative treatment option, particularly for intracellular targets. The two types of TOs, antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs), distribute highly into tissues, especially into the liver and the kidneys. However, molecular processes at the cellular level such as the uptake into the cell, endosomal escape, binding to the target mRNA, and redistribution back to the systemic circulation are not well characterized because experimental data and assays are lacking. We developed a whole-body PBPK model for TOs and verified the predictive performance against clinically observed data for three ASOs and five siRNAs. The predicted concentration-time profiles were in accordance with the clinically observed data for all investigated TOs, and all pharmacokinetic parameters were predicted within twofold. Sensitivity analysis with the evaluated PBPK model revealed that the endocytosis uptake rate and the fraction unbound in plasma impact the peak concentration (Cmax), time to Cmax (tmax), and the area under the curve (AUC) of a subcutaneously administered ASO, whereas the redistribution rate and the nuclease clearance had minor to no impact. The mathematical model can guide the development of required in vitro assays for key parameters to better understand the pharmacokinetics of TOs. PBPK models, parameterized with reliable in vitro data, could be used in the future to predict the pharmacokinetics in special populations with limited clinical data to ensure a safe and effective therapy.
Insights
A new whole-body physiologically based pharmacokinetic (PBPK) model accurately predicts therapeutic oligonucleotide (TO) concentrations. This model aids in understanding the pharmacokinetics of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) for improved drug development.
Area of Science:
- Pharmacology
- Biotechnology
- Computational Biology
Background:
- Therapeutic oligonucleotides (TOs), including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are promising for targeting intracellular molecules.
- Key cellular processes like uptake, endosomal escape, and target binding for TOs remain poorly understood due to limited experimental data.
- Accurate pharmacokinetic characterization is crucial for the safe and effective development of TO-based therapies.
Purpose of the Study:
- To develop and validate a whole-body physiologically based pharmacokinetic (PBPK) model for therapeutic oligonucleotides (TOs).
- To assess the predictive performance of the PBPK model against clinical data for various ASOs and siRNAs.
- To identify critical parameters influencing TO pharmacokinetics through sensitivity analysis.
Main Methods:
- Development of a whole-body PBPK model specifically designed for therapeutic oligonucleotides.
- Validation of the model using clinical concentration-time data from three ASOs and five siRNAs.
- Conducting sensitivity analyses to determine the impact of various parameters on pharmacokinetic outcomes.
Main Results:
- The PBPK model demonstrated accurate predictions for concentration-time profiles of all tested TOs, with pharmacokinetic parameters predicted within twofold of observed values.
- Sensitivity analysis indicated that endocytosis uptake rate and fraction unbound in plasma significantly affect Cmax, Tmax, and AUC for subcutaneously administered ASOs.
- Redistribution rate and nuclease clearance showed minimal impact on the pharmacokinetic parameters evaluated.
Conclusions:
- The developed PBPK model provides a robust framework for understanding and predicting TO pharmacokinetics.
- The model can guide the development of essential in vitro assays to determine key pharmacokinetic parameters.
- PBPK modeling, when parameterized with in vitro data, holds potential for predicting TO pharmacokinetics in special populations, ensuring therapeutic safety and efficacy.
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