Unravelling the pharmacokinetics of oligonucleotides by using a PBPK model

Description of session (include background & scientific importance): Therapeutic oligonucleotides are emerging modalities. The two types, antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs), distribute highly into tissues, especially into the liver and kidney. However, molecular processes on the cellular levels such as uptake into the cell, endosomal escape, binding to the target, and redistribution back to the systemic circulation are not well characterized because experimental data are lacking. A mathematical model combined with preclinical and clinical data can be used to investigate and understand cellular processes. We developed a whole-body PBPK model, parameterized it with available data, and verified the predictive performance against clinically observed data for different ASOs and siRNAs. The evaluated model was used to investigate the dependency of the oligonucleotide pharmacokinetics on the uptake and redistribution rate. Furthermore, we used the PBPK model to predict the pharmacokinetics in different ethnic groups (e.g. Japanese) and in organ impairment. The developed PBPK model highlights the use of modelling tools to understand the pharmacokinetics of novel therapeutic modalities. This is of high scientific importance, because therapeutic oligonucleotides are an emerging drug class.
The presentation will provide an in-depth overview about the development and verification of an oligonucleotide model, the understanding of the importance of cellular uptake and systemic redistribution on the pharmacokinetics of therapeutic oligonucleotides, and the prediction in different populations to ensure safe and effective therapy in different ethnic and disease groups.