(T-001) A Model-based Pharmacokinetic Simulation Tool to Aid Dose Selection of Antisense Oligonucleotides Administered Intrathecally in Pediatrics

Michael Monine, Ph.D. – Scientific Director, Clinical Pharmacology and Pharmacometrics, Biogen Inc.; Natalie Schmitz, Ph.D. – Principal Scientist, Clinical Pharmacology and Pharmacometrics, Biogen Inc.; Yan Xu, MD, Ph.D., FCP – Senior Director, Clinical Pharmacology and Pharmacometrics, Biogen Inc.; Ivan Nestorov, Ph.D. – Executive Director, Head of Pharmacometrics, Clinical Pharmacology and Pharmacometrics, Biogen Inc.; Shirley Wu, Pharm.D. – Principal Scientist, Clinical Pharmacology and Pharmacometrics, Biogen Inc.

Objectives: Intrathecally (IT)-administered antisense oligonucleotides (ASOs) targeting neuromuscular disorders have demonstrated promising clinical effects in pediatrics. However, selection of pediatric doses for IT-administered ASOs is challenging due to limited data available on the central nervous system (CNS) distribution of IT ASOs. A physiologically-based pharmacokinetics (PBPK) model scaled to the effective volumes of the CNS organs and cerebrospinal fluid (CSF) can help with predicting pediatric biodistribution. The current study aims to develop a PBPK and pharmacodynamic (PD) modeling and simulation tool to inform IT-ASO dosing in pediatric subpopulations.

Methods: The PBPK model for IT ASOs [1] was implemented using mrgsolve package in an R Shiny application. Virtual pediatric subjects at the different age categories (neonates, infants, children, and adolescents) were created, using literature volume growth relationships for spinal CSF, cranial CSF, spinal cord tissues, and brain tissues [2-3]. The application predicted ASO exposures at user-specified dosing regimens in various compartments across different age ranges. Furthermore, the predicted ASO concentrations were used as an input to the direct or indirect exposure-response models to evaluate mRNA and protein reduction from baseline in target CNS tissues assuming typical values for Emax, IC50 and target turnover rates.

Results: Age-dependent changes of CNS volumes may affect ASO CNS distribution and thus response. These changes were most prominent in the younger age groups. An R Shiny application was developed which has the capability to predict ASO exposures in a wide age range of pediatric populations to aid with pediatric dose selection.

Conclusions: The ASO PBPK model incorporating CSF and CNS volume growth data provides semi-mechanistic predictions of PK and PD for IT ASO therapeutics in pediatric subjects. This simulation tool is intended to aid in ASO pediatric dose selection particularly for neonates and infants.

Disclosures: All authors were employees of Biogen at the time of the study and may own stock of Biogen.

Citations: Citations:
[1] Monine et al. J Pharmacokinet Pharmacodyn. 2021 Oct; 48(5):639-654.
[2] Jang et al. Paediatr Anaesth. 2019 Jan;29(1):92-97.
[3] Vannucci and Vannucci. Am J Phys Anthropol. 2019 Feb;168(2):247-261.