Effect of vepdegestrant, a PROTAC oestrogen receptor degrader, on dabigatran and rosuvastatin pharmacokinetics in healthy participants.

AIMS: To evaluate the effects of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) oestrogen receptor degrader, on the pharmacokinetics of dabigatran (a P-glycoprotein [P-gp] substrate) and rosuvastatin (a breast cancer resistance protein [BCRP] substrate).

METHODS

In two phase 1, open-label, two-period, fixed-sequence studies, healthy adult participants received a single oral dose of dabigatran etexilate 75 mg or rosuvastatin 10 mg alone and with a single dose of vepdegestrant 200 mg. Serial plasma samples were collected after dosing, and pharmacokinetic parameters for dabigatran and rosuvastatin were estimated by standard noncompartmental analysis.

RESULTS

Coadministration of the P-gp substrate dabigatran etexilate with vepdegestrant increased dabigatran area under the concentration-time curve (AUC) from time 0 to infinity by 98% and maximum plasma concentration (Cmax) by 92%. Coadministration of the BCRP substrate rosuvastatin with vepdegestrant increased rosuvastatin plasma AUC from time 0 to time of the last measurable concentration by 11% and Cmax by 21%.

CONCLUSIONS

Coadministration with vepdegestrant doubled dabigatran exposure and resulted in a minor increase (11%) in rosuvastatin exposure in humans.