Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

Abstract

AbstractThe objective of the current study was to identify potential drug–drug interactions (DDIs) with the drug candidate fb‐PMT, a novel anticancer thyrointegrin αvß3 antagonist. This was accomplished by using several in vitro assays to study interactions of fb‐PMT with both cytochrome P450 (CYP) enzymes and drug transporters, two common mechanisms leading to adverse drug effects. In vitro experiments showed that fb‐PMT exhibited weak reversible inhibition of CYP2C19 and CYP3A4. In addition, fb‐PMT did not show time‐dependent inhibition with any of the seven CYP isoforms tested, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. Human liver microsomal incubations demonstrated that fb‐PMT is stable. Potential transporter‐mediated DDIs with fb‐PMT were assessed with two ATP binding cassette (ABC) family transporters (P‐glycoprotein and breast cancer resistance protein) using Caco2 cells and seven solute carrier family (SLC) transporters (organic cation transporter OCT2, organic anion transporters OAT1 and OAT3, organic anion transporter peptides OATP1B1 and OATP1B3, and the multidrug and toxic extrusion proteins MATE1 and MATE2‐K using transfected HEK293 cells). Fb‐PMT was not a substrate for any of the nine transporters tested in this study, nor did it inhibit the activity of seven of the transporters tested. However, fb‐PMT inhibited the uptake of rosuvastatin by both OATP1B1 and OATP1B3 with half‐maximal inhibitory concentrations greater than 3 and less than 10 μM. In summary, data suggest that the systemic administration of fb‐PMT is unlikely to lead to DDIs through CYP enzymes or ABC and SLC transporters in humans.