e13013 Background: Hot flashes or vasomotor symptoms (VMS) are a common side effect of hormone deprivation (HD) therapy. Up to 80 % of cancer patients treated with tamoxifen (antiestrogen treatment) or leuprolide (androgen deprivation) have VMS. In some cases, patients discontinue HD therapy due to VMS severity and lower quality of life; therefore, reducing VMS is critical for patient compliance. NK3 receptor (NK3R) antagonists have previously been shown to reduce VMS in postmenopausal women. ACER-801 is a candidate NK3R antagonist drug intended to alleviate VMS severity when used with HD therapy. We used Quantitative Systems Pharmacology (QSP) modeling to predict the likely efficacy of ACER-801 in patients on HD therapy and evaluate the potential of hepatic drug-drug interactions between ACER-801 and tamoxifen or leuprolide. Methods: The model is composed of KNDy neurons in the arcuate nucleus with NKB, dynorphin, and estradiol effects on KNDy neurons, HPG axis, sex hormones, and neuroendocrine feedback. ACER-801, tamoxifen, and leuprolide PK, PD, and hepatic metabolism are included in the model. The model was developed, qualified, and tested using literature data. A tamoxifen-treated postmenopausal female virtual patient (VP) and leuprolide-treated male VP were created based on typical patients included in clinical trials. VMS severity and frequency were estimated based on the level of NKB binding to NK3R. Results: In the male VP, simulated leuprolide administration induced hypertrophy of KNDy neurons and VMS over six months. Coadministration of ACER-801 with leuprolide reduced VMS frequency and severity to near 0 in short-term (5-week) simulations. Simulations predict ACER-801 will not alter leuprolide metabolism nor increase plasma testosterone concentrations. Tamoxifen treatment increased VMS by 15% in simulations with the postmenopausal VP. Coadministration of ACER-801 with tamoxifen in this VP reduced VMS by 75% compared to tamoxifen monotherapy. ACER-801 had minimal effects on plasma estradiol concentrations in the postmenopausal VP. Drug-drug interactions between ACER-801 and tamoxifen were dependent on the simulated bioavailability of ACER-801. Using current estimates of ACER-801 bioavailability in the model, the hepatic concentration of ACER-801 had limited effects on tamoxifen metabolism, which are not expected to necessitate dose adjustments. Conclusions: Using a QSP neurobiology model as a research tool enabled us to evaluate the efficacy of the NK3R antagonist, ACER-801, to treat HD therapy-induced VMS. Simulations show ACER-801 may be highly efficacious for the treatment of induced-VMS. The research provided estimates of DDI with ACER-801 and tamoxifen and what clinical experiments would be needed to confirm those estimates.