ArticleJournal of pharmacokinetics and pharmacodynamics2025
Cross-species translational modelling of targeted therapeutic oligonucleotides using physiologically based pharmacokinetics.
Article in Journal of pharmacokinetics and pharmacodynamics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
2 citing papers in PubMed.
- Pharmacokinetic/Pharmacodynamic Translation and Model-Informed Drug Development for Oligonucleotide Therapeutics.Journal of clinical pharmacology · 2026Review
- Tissue Pharmacokinetics of Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2026Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oligonucleotide therapeutics hold promise for targeted gene silencing, yet achieving optimal tissue-specific delivery remains challenging. This study introduces a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to predict tissue uptake dynamics of both conjugated (targeted) and unconjugated oligonucleotides across species. The model incorporates two uptake pathways: a non-saturable nonspecific pathway for all oligonucleotides and receptor-mediated endocytosis (RME) specific to conjugated molecules. Parameters for nonspecific uptake were derived from plasma and tissue concentration data of unconjugated antisense oligonucleotides (ASOs) in rats, while RME parameters for N-acetylgalactosamine (GalNAc)-conjugated oligonucleotides targeting the asialoglycoprotein receptor (ASGPR) were obtained from literature. Model validation against experimental data for conjugated and unconjugated ASOs and small interfering RNAs (siRNAs) in rats and mice demonstrated good predictive performance, 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. Local sensitivity analyses identified key parameters and processes influencing organ uptake, including the unbound plasma fraction and receptor-mediated uptake efficiency. Simulations highlighted the potential of sustained-release formulations to improve targeting specificity by mitigating receptor saturation. This is the first whole-body PBPK model to describe oligonucleotide pharmacokinetics across species and modalities. The model provides critical mechanistic insights to optimize tissue-specific delivery, guide formulation strategies, and enhance therapeutic outcomes for targeted oligonucleotide therapeutics.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.