Abdallah Derbalah1, Felix Stader1, Cong Liu1, Adriana Zyla1, Armin Sepp1
1Certara UK Ltd., Certara Predictive Technologies devision
Introduction: Oligonucleotide therapeutics offer a powerful approach for gene silencing across various disease areas, yet achieving efficient and tissue-specific delivery remains a critical challenge. Due to their large molecular size and hydrophilic nature, oligonucleotides struggle with cellular uptake, limiting their therapeutic potential beyond the liver. The success of N-acetylgalactosamine (GalNAc)-conjugated oligonucleotides in liver-targeted delivery via the asialoglycoprotein receptor (ASGPR) underscores the potential of receptor-mediated uptake for tissue-specific targeting [1]. Extending this paradigm to other tissues requires a quantitative framework to evaluate receptor expression, saturation kinetics, and delivery efficiency. This study presents a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to predict oligonucleotide tissue distribution and highlights how sustained-release formulations can mitigate receptor saturation, thereby enhancing targeting specificity and reducing off-target exposure. Objectives: To develop and apply a mechanistic PBPK model for evaluating tissue-specific oligonucleotide delivery, with a focus on strategies for mitigating receptor saturation effects on tissue targeting specificity. Methods: This study utilized a cross-species whole-body physiologically based pharmacokinetic (PBPK) modeling platform implemented in QSP Designer (V2.0.0.53; Certara, Sheffield, UK) [2]. The two-pore biologics platform incorporates physiological and mechanistic knowledge governing the pharmacokinetics of large molecules across four species: mice, rats, monkeys, and humans. The model was adapted to incorporate oligonucleotide-specific pharmacokinetics, including two key uptake pathways: non-saturable nonspecific uptake and receptor-mediated endocytosis (RME) for conjugated oligonucleotides. Model parameters for nonspecific uptake were estimated using plasma and tissue concentration data of unconjugated antisense oligonucleotides (ASOs) in rats [3]. Model validation was performed using experimental plasma and tissue data for conjugated and unconjugated ASOs and small interfering RNAs (siRNAs) in rats and mice [4-9]. Subcutaneous (SC) administration was mechanistically modelled through a separate tissue component for the SC administration site which inherited physiological parameters from the adipose tissue. This was then validated against plasma concentration data from a SC administered unconjugated ASO in mice [10]. The RME model was validated against IV and SC administered GN3-conjugated ASOs [11] and siRNAs [12]. Local sensitivity analyses was used to identify key parameters influencing organ uptake. Model simulations were used to explore the impact of various strategies on receptor saturation and targeting specificity. Results: The model was trained on a dataset of 136 observations, capturing plasma and tissue concentrations across multiple organs, including liver, kidney, lung, pancreas, spleen, heart, muscle, bone, and gut. The validation dataset encompassed 394 observations, spanning different compounds, doses, and administration routes. Predictive performance was robust, with median predicted-to-observed AUC ratios of 0.84 (Interquartile Range [IQR] 0.434–1.22) in rats and 0.629 (IQR 0.3–1.6) in mice. Sensitivity analysis highlighted that the unbound plasma fraction and receptor-mediated uptake efficiency were key determinants of tissue exposure. Simulations revealed that sustained-release formulations can mitigate receptor saturation effects, improving targeting specificity and reducing off-target exposure. Conclusions: This study presents the first whole-body PBPK model capable of describing oligonucleotide pharmacokinetics across species and modalities. The model provides critical mechanistic insights into tissue-specific targeting and highlights the potential of sustained-release formulations to optimize therapeutic outcomes by reducing receptor saturation and enhancing specificity. PBPK modelling serves as a powerful tool to guide formulation strategies and accelerate the development of next-generation oligonucleotide therapeutics.
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Reference: PAGE 33 (2025) Abstr 11403 [www.page-meeting.org/?abstract=11403]
Poster: Drug/Disease Modelling - Absorption & PBPK