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