Predictive modelling and simulation for taming the chance and luck in biologics drug discovery
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 pharmacologi...
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| Format: | Article |
| Language: | English |
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Estonian Academy Publishers
2023-10-01
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| Series: | Proceedings of the Estonian Academy of Sciences |
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| Online Access: | https://kirj.ee/wp-content/plugins/kirj/pub/proc-4-2023-371-381_20231024125333.pdf |
| Summary: | 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. CrossÂspecies/crossÂmodality physiologicallyÂbased pharmacokinetics (PBPK) framework aims to provide the first principle quantitative predictions for the first two of the declared Pillars. The approach is based on twoÂpore hypothesis of extravasation, further developed with PBPK in mind and parameterized for fractional tissue lymph flow rates using rodent data. The biologics 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. |
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| ISSN: | 1736-6046 1736-7530 |