A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides.

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.
Competing Interests: YH and MV are currently employed by Takeda. Authors DP and SI were employed by Takeda. AL is a professor at the University of Illinois and President of System Science Inc. This study received funding from Takeda. AL had previously served as consultant to Takeda.
(Copyright © 2023 Linninger, Barua, Hang, Iadevaia and Vakilynejad.)