A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration

The objective of this work is to advance fundamental understanding of whole-body distribution of IT-administered ASOs. We propos e a physiologically-based pharmacokinetic modeling approach to describe the distribution along the neuroaxis based on PK data from non-human primate (NHP) studies. We aim to understand the key processes that drive and limit ASO access to the CNS target tissues. To elucidate the trade-off between par ameter identifiability and physiological plausibility of the model, several alternative model structures were chosen and fitted to the NHP data. The model analysis of the NHP data led to important qualitative conclusions that can inform projection to human. In particular, the model predicts that the maximum total exposure in the CNS tissues, including the spinal cord and brain, is achieved within two days after the IT injection, and the maximum amount absorbed by the CNS tissues is about 4% of the administered IT dose. This amount greatly exceeds the CNS exposures delivered by systemic adminis tration of ASOs. Clearance from the CNS is controlled by the rate of transfer from the CNS tissues back to CSF, whereas ASO degradation in tissues is very slow and can be neglected. The model also describes local differences in ASO concentration emerging along the spinal CSF canal. These local conce ntrations need to be taken into account when scaling the NHP model to human: due to the lengthier human spinal column, inhomogeneity along the spinal CSF may cause even...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research