Prediction of Biopharmaceutical Characteristics of PROTACs using the ANDROMEDA by Prosilico Software

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Published: 2022-09-23

Formatted citation

Fagerholm U, Hellberg S, Alvarsson J, Spjuth O. Prediction of Biopharmaceutical Characteristics of PROTACs using the ANDROMEDA by Prosilico Software.
bioRxiv. 2022.09.22.509053 (2022). DOI: 10.1101/2022.09.22.509053


Background: PROTACs are comparably large and flexible compounds with limited solubility (S) and permeability (Pe). It is crucial to better understand, predict and optimize their human clinical pharmacokinetics (PK). Methods: The main objective was to use the ANDROMEDA by Prosilico software to predict the human clinical in vivo dissolution potential (fdiss) and fraction absorbed (fa) of 23 PROTACs at a dose level of 50 mg and to explore whether there is any relationship between in vitro S and in silico predicted in vivo fdiss. Results: In silico predictions showed that the PROTACs are effluxed by intestinal transporters and have limited fdiss (34 to 98 %), permeability and fa (13 to 58 %) in man. For some PROTACs this may be a major obstacle and jeopardize the clinical development programs, especially in cases of required high oral dose. A modest relationship between in vitro S and predicted in vivo fdiss was demonstrated (R2=0.26). Predicted human fa (27 %) and oral bioavailability (20 %) of ARV-110 (a PROTAC with some available in vivo PK data in rodents and man) were consistent with data obtained in rodents (estimated fa approximately 30-40 %; measured oral bioavailability 27-38 %). Laboratories were unable to quantify S for 7 (30 %) of the PROTACs. In contrast, ANDROMEDA could predict parameters for all. Conclusion: ANDROMEDA predicted fdiss and fa for all the chosen PROTACs and showed limited fdiss, Pe and fa and dose-dependent fdiss and fa. One available example shows promise for the applicability of ANDROMEDA for predicting biopharmaceutics of PROTACs in vivo in man. Weak to modest correlations between S and fdiss and a considerable portion of compounds with non-quantifiable S limit the use of S-data to predict the uptake of PROTACs.