A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides

Andreas A Linninger; Dipak Barua; Yaming Hang; Sergio Iadevaia; Majid Vakilynejad

doi:10.3389/fphys.2023.1130925

A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides

Front Physiol. 2023 Jun 2:14:1130925. doi: 10.3389/fphys.2023.1130925. eCollection 2023.

Authors

Andreas A Linninger¹, Dipak Barua², Yaming Hang², Sergio Iadevaia², Majid Vakilynejad²

Affiliations

¹ University of Illinois at Chicago, Chicago, IL, United States.
² Takeda Pharmaceuticals, Cambridge, MA, United States.

Abstract

Intrathecal administration is an important mode for delivering biological agents targeting central nervous system (CNS) diseases. However, current clinical practices lack a sound theorical basis for a quantitative understanding of the variables and conditions that govern the delivery efficiency and specific tissue targeting especially in the brain. This work presents a distributed mechanistic pharmacokinetic model (DMPK) for predictive analysis of intrathecal drug delivery to CNS. The proposed DMPK model captures the spatiotemporal dispersion of antisense oligonucleotides (ASO) along the neuraxis over clinically relevant time scales of days and weeks as a function of infusion, physiological and molecular properties. We demonstrate its prediction capability using biodistribution data of antisense oligonucleotide (ASO) administration in non-human primates. The results are in close agreement with the observed ASO pharmacokinetics in all key compartments of the central nervous system. The model enables determination of optimal injection parameters such as intrathecal infusion volume and duration for maximum ASO delivery to the brain. Our quantitative model-guided analysis is suitable for identifying optimal parameter settings to target specific brain regions with therapeutic drugs such as ASOs.

Keywords: antisense oligodeonucleotides; central nervous system; computational fluid dynamics; intrathecal delivery; pharmacokinetic modeling and simulation.

Grants and funding

This study received funding from Takeda. AL had previously received consulting funding from Takeda. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.