Predicting the pharmacokinetics and pharmacodynamics of antisense oligonucleotides: an overview of various approaches and opportunities for PBPK/PD modelling

ABSTRACT

Introduction

Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.

Areas covered

A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023). ASO PK and PD in animals and humans and modeling approaches including physiologically based (PB) are summarized; and relevance and impacts of PBPK/PD modeling are assessed.

Expert Opinion

Allometric scaling and compartmental PK/PD modeling have been successful to predict human ASO PK/PD, addressing most R&D needs. Understanding tissue distribution of ASOs can be crucial for their efficacy and safety especially for intrathecal (IT), pulmonary, or other local routes. PBPK/PD modeling is expected to improve such understanding, for which, efforts have been sporadic. However, developing a PBPK/PD model requires careful review of known biology/pharmacology and thoughtful experimental designs. Resulting models have the potential to predict target/specified tissue exposures and responses in human adults and pediatrics. Ultimately, a PBPK/PD modeling approach can lead to more efficient and rational clinical development, resulting in well-informed decision making and a shortened timeline.

KEYWORDS:

• Antisense oligonucleotide
• pharmacokinetics
• pharmacodynamics
• physiologically-based modeling
• prediction of human effects

Article highlights

• The PK of ASOs within a similar chemistry class (i.e. 2′-MOE) are remarkably similar independent of nucleotide sequence and animal species, which makes their PK in humans highly predictable and share similar pharmacokinetic characteristics such as comparable plasma PK and tissue disposition profiles.

• Following systemic administration of 2′-MOE ASOs, the parallel elimination phases and similar terminal elimination half-lives in plasma and tissues allow post-distribution plasma concentrations to be used as a surrogate of tissue concentrations. Prediction of human PK can be scaled from monkey based on normalization of doses to body weight.

• Following intrathecal administration of 2′-MOE ASOs, a PK scaling factor based on differences in the cerebrospinal fluid (CSF) volume between animals and humans can be utilized.

• Exposure-response PD data obtained from transgenic mice has been shown to be comparable to humans and can be used to inform drug effect parameters in PK/PD models for human predictions.

• The application of PBPK/PD modeling approach to ASOs is still rather limited. More data is needed, especially mechanistic studies to quantitatively inform tissue partitioning and metabolic parameters based on the unique physicochemical and PK properties of ASOs, as well as tissue concentration versus time course data.

• The emergence in the development of novel conjugated ASOs as well as delivery routes provides a window of opportunity for PBPK/PD modeling of ASOs with potential advantages in prediction of drug concentrations in target organs, interspecies-scaling, and pediatric and route to route extrapolations.

Declaration of interests

All authors are employees of Ionis Pharmaceuticals, Inc. and hold stocks or stock options of Ionis Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

Data sharing not applicable – no new data generated.

Acknowledgments

We thank T Reigle, W Sullivan, T Holmes, for their assistance with figures and administrative support, and F Bennett for his scientific input for Figure S3.

Additional information

Funding

This paper was not funded.