Abstract 4347: Preclinical evaluation of pharmacokinetic interactions among nebivolol, dasatinib and devimistat in mice

Abstract Breast cancer ranks as the most frequently diagnosed cancer in 157 of 185 countries. It accounts for 30% of all new female cancers annually, with triple-negative breast cancer (TNBC) comprising 10-15% of the cases. TNBC is particularly aggressive, with rapid growth and spread, limited treatment options, and a worse prognosis. Due to the lack of markers, TNBC is challenging to treat, and monotherapies are often ineffective; instead, combination therapies with drugs with different mechanisms of action may offer more effective options. In the previous study, G protein-coupled receptor-targeting drugs were evaluated using high throughput screening. Nebivolol (NBV), a third generation β-blocker, was identified as a potential inhibitor against TNBC metastasis. This study investigated the pharmacokinetics (PK) of NBV in combination with dasatinib (DAS), a multi-kinase inhibitor, and devimistat (CPI), a mitochondrial tricarboxylic acid cycle inhibitor, respectively, in FVB healthy mice, focusing on the potential drug-drug interaction (DDI). In this study, FVB mice were randomly assigned to 5 groups (NBV, DAS, CPI, NBV+DAS and NBV+CPI, n=5 each). The compounds were administered via intraperitoneal injection at single doses of NBV at 4 mg/kg, DAS at 10 mg/kg, and CPI at 12 mg/kg, for each group. Blood samples were collected at 20 min, 1 h, 3 h, 6 h, 8 h, and 23 h post dose and quantified using LC-MS/MS assay (Sciex 5500). Data was analyzed using Phoenix (8.5.1) and GraphPad Prism (10). Statistical analysis of PK parameters was performed using ANOVA followed by Tukey post hoc test or t-test, for significance at p<0.05. The results indicated, in the NBV and DAS combination group, the half-life of NBV (Mean+SD) significantly increased to 5.32±1.72 hours, from 3.11±0.27 hours in NBV alone group, likely due to a higher distribution volume (V) and lower clearance (CL), which were not statistically significant due to large variations. The area under curve (AUC) remained comparable in combination treatment. The PK of DAS was unaffected by NBV. In the combination of NBV and CPI, the PK parameters of NBV were unaffected, whereas the CL of CPI significantly decreased in the combination group (70.29±30.32 L/h), from that in CPI alone group (142.32±49.35 L/h). CPI distribution volume decreased (124.51±90.18 L) in the combination group versus 1107.11±1379.40 L in the alone group. However, this change in V was not statistically significant due to a large variation. The AUC of CPI significantly increased to 201.72±92.25 h*ng/mL, compared to 87.62±22.21 h*ng/mL in CPI alone group. In summary, DDIs were observed among NBV, DAS, and CPI. Co-administration with DAS slowed the NBV elimination, suggesting that NBV accumulation would be considered when used alongside DAS. Additionally, CPI exposure significantly increased in the presence of NBV, indicating that dose adjustments may be necessary in combination therapies. Citation Format: Airong Li, Mikayla Skillman, Fatima Dagher, Amir Mohammad Gholizadeh, Emanuel Baltrip, Junghwa Park, Meghana Trivedi, Diana S.-L. Chow. Preclinical evaluation of pharmacokinetic interactions among nebivolol, dasatinib and devimistat in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4347.