Prediction of PK/PD for Intrathecally-Administered Antisense Oligonucleotides

Intrathecal (IT) administration of antisense oligonucleotides (ASOs) has become an efficient method for targeting neurodegenerative and neuromuscular disorders. Dose projection for IT-administered ASOs in humans requires accurate estimation of exposures at target sites within the central nervous system (CNS). Since human CNS tissues are practically inaccessible to analyze for ASO concentrations and target engagement in vivo, animal data and animal-to-human scaling become of critical importance in guiding dose selection for first-in-human (FIH) studies.

Biochemical mechanisms by which CSF-carried drugs are distributed across spinal cord and brain regions still remain poorly characterized. Additional risks stem from uncertainty in translation of target engagement between species and contribution of pharmacodynamic (PD) response at a tissue level to changes in clinical endpoints.

Recently, advancements were made in the development of semi-empirical compartmental and mechanistic models for IT ASOs. We will review several modeling approaches with a particular focus on our preclinical physiologically-based pharmacokinetic (PBPK) model that has been developed to characterize the whole-body distribution of IT ASOs in non-human primate (NHP) studies. We will discuss scaling approaches and consider several clinical study examples to illustrate adequacy of the PBPK/PD modeling approach.