Predictive modelling and simulation for taming the chance and luck in biologics drug discovery/Bioloogiliste makromolekulide fusioloogiline farmakokineetika

• Published in: Proceedings of the Estonian Academy of Sciences Vol. 72; no. 4; p. 371
• Main Author: Sepp, Armin
• Format: Journal Article
• Language: English
• Published: Estonian Academy Publishers 01.12.2023
• Subjects: Biosimilar pharmaceuticals; Drug discovery; Technology application; United Kingdom
• ISSN: 1736-6046
• DOI: 10.3176/proc.2023.4.02

Three Pillars of Survival paradigm in the pharmaceutical drug discovery stipulates that a drug candidate is more likely to reach Phase III if it meets the following criteria: 1) it reaches the required tissue compartment, 2) engages the desired target, 3) triggers the desired downstream pharmacological effect. This paper describes the progress made along this track for biologics, in the first instance for monoclonal antibodies, their fragments and therapeutic proteins in general. Cross-species/cross-modality physiologically-based pharmacokinetics (PBPK) framework aims to provide the first principle quantitative predictions for the first two of the declared Pillars. The approach is based on two-pore hypothesis of extravasation, further developed with PBPK in mind and parameterized for fractional tissue lymph flow rates using rodent data. The biologies PBPK framework is validated by accurately predicting the tissue distribution and elimination properties of normal and modified antibodies and their fragments in primate and human studies. Keywords: physiologically-based pharmacokinetics, PBPK, biologies, therapeutic antibodies, therapeutic proteins. Ravimiarendus on valdkond, mis uhelt poolt toetub tippteadusele ning teisalt mojutab sumbiootiliselt ka selle prioriteete ja arengut. Bioloogiliste ravimite fusioloogiline farmakokineetika on valdkond, mis juhatab sisse kvantitatiivse, mehhanistliku (predictive) temaatika ravimiarenduse metoodikas ning loob ka tugiraamistiku, millele toetudes saab fundamentaalteaduse votmes analuusida organismi erinevate osade funktsioneerimist uhtse tervikuna, seda nii normaalses kui ka patoloogilises fusioloogilises kontekstis.