Senior Research Scientist Certara UK Limited Sheffield, England, United Kingdom
Oligonucleotides are a promising novel treatment option because of their unique mechanism of action and therapeutic potential in many disease areas. Both, antisense oligonucleotides (ASO) and silencing RNA (siRNA), can modulate mRNA and thus, any target protein. The pharmacokinetics of oligonucleotides depends on their molecular size, polarity, and chemical modifications. One of the challenges is to understand the distribution of oligonucleotides and their interaction with the target. Having mechanistic models that can accurately predict the distribution, metabolism, and excretion of oligonucleotides in vivo is thus, highly desirable. Mechanistic physiologically based pharmacokinetic (PBPK) models that integrate physiological, anatomical, and biochemical information are already used for modelling both small and large molecules and can be used to simulate the time-course of oligonucleotides disposition in different organs and tissues, considering their specific characteristics. By incorporating relevant mechanisms such as cellular uptake, redistribution out of the cell, enzymatic degradation, and elimination pathways, the PBPK models can be used to predict and understand oligonucleotide PK. The PBPK models, informed by both in vitro and in vivo data, can handle ASOs and small interfering RNAs. This presentation provides an in-depth overview of involved processes and how PBPK models are applied to predict oligonucleotide PK.
Learning Objectives:
Upon completion, participants got an overview about oligonucleotide drugs.
Upon completion, participants will be familiar with the physiological processes that have an impact on the pharmacokinetics of oligonucleotides.
Upon completion, participants will become familiar with physiological and system parameters affecting oligonucleotides pharmacokinetics.
Upon completion, participants will understand the structure and parameters of a physiologically-based pharmacokinetic model for oligpnucleotides.
Upon completion, participants will understand how physiologically-based pharmacokinetic models can be used to predict oligonucleotides disposition in different tissues.