Abstract 3158: Pharmacokinetic and biodistribution evaluation of nebivolol and dasatinib in the 4T1 triple-negative breast cancer model: Implications for drug-drug interaction

Abstract Background: In our recent in-vitro study, nebivolol (NEB) and dasatinib (DAS) synergistically inhibited the growth of 4T1 cell line, which is a murine mammary carcinoma cell line used to study triple-negative breast cancer (TNBC). However, the in vivo disposition and potential for drug-drug interactions (DDI) are not well defined. This study aimed to characterize the pharmacokinetics (PK) and biodistribution of NEB and DAS in 4T1 tumor-bearing mice and evaluate whether co-administration modifies plasma or tissue concentrations. Methods: Female BALB/c mice (7-8 weeks) were implanted with 4T1 cells orthotopically and treated with NEB (n=5), DAS (n=5), or NEB+DAS (n=6). The regimen was NEB 10 mg/kg once a day and DAS 20 mg/kg twice a day, 5 days/week for 3 weeks. After the last dose, blood was collected at multiple time points and tissues (tumor, liver, kidney, lung, spleen, heart, pancreas, and brain) were harvested at the end. Drug concentration was quantified using a validated LC-MS/MS method. PK parameters were generated by Phoenix (8.5.1) and GraphPad 10 was used to generate the PK profile and statistical analysis. Results: Co-administration significantly increased NEB exposure in blood, of which the area under curve (AUC normalized by dose) was 229.45±150.98 hr*ng/mL/(mg/kg), compared to 44.51±10.21 hr*ng/mL/(mg/kg) in the NEB alone group (p