Abstract 4342: The lymphatic system plays a major role in the absorption of subcutaneously administered trastuzumab in a lymph-duct cannulated rat model

Abstract Introduction: The lymphatic system plays a key role in the metastasis of a number of cancers, such as certain types of breast cancer, lung cancer, and colorectal cancer. Drug delivery to the lymphatics may co-localize high concentrations of therapeutic agents and the biological targets (cancer cells or immune cells) in a relatively confined area, thereby providing opportunities for the inhibition of lymphatic metastasis. However, such targeted delivery is usually difficult to achieve since drug molecules mainly circulate via the blood stream instead of the lymphatics. A number of preliminary studies on the pharmacokinetic behaviors of subcutaneously administered biologicals suggested that the lymphatic system served as a main conduit for the absorption of large molecule drugs. The current study aims to examine the absorption pathways (blood vs lymph) after subcutaneous administration of two marketed products of the same anti-HER2 monoclonal antibody drug trastuzumab (Herceptin for IV and Herceptin for SC). Method: In vivo pharmacokinetic studies were conducted using a rat model with cannulas in thoracic lymph duct, carotid artery and jugular vein. Herceptin IV (intravenous formulation) and Herceptin SC (subcutaneous formulation) were administered to two groups of animals to the footpad at a dose of 2.5 mg/kg trastuzumab (both diluted to a concentration of 21 mg/ml using saline before injection). Lymph fluid from the thoracic duct and blood from the carotid artery were collected, with fluid loss compensated through jugular vein using saline. Results: More than 70% of the subcutaneously administered dose was recovered in thoracic lymph for both formulations of trastuzumab in rats over 36 hours. Notably, trastuzumab concentration in the lymph of the cannulated group was approximately ten times higher than that in the plasma collected from the same animals. Furthermore, following subcutaneous administration, Herceptin SC formulation demonstrated faster absorption profile compared to the IV formulation, with trastuzumab Cmax in lymph 3 times higher (∼150 μg/ml for Herceptin SC vs 50 μg/ml for Herceptin IV), and Tmax in lymph 1 hour earlier (1h for Herceptin SC vs 2h for Herceptin IV). The faster absorption and higher lymphatic transport are potentially due to the presence of rHuPH20 in the SC product that facilitated disperse of the antibody molecules in the subcutaneous interstitial spaces. Conclusion: The study confirms the lymphatics is the main absorption pathway following subcutaneous administration of trastuzumab, regardless of the formulation type (IV or SC). This results in markedly high concentrations of trastuzumab in the draining lymphatics, and the co-localization of the drug molecules with potentially disseminated tumor cells and immune cells within the tumor-draining lymphatics may provide an opportunity for enhanced therapeutic outcomes. Citation Format: Junyi Pei, Xiaoxuan Fei, Luojuan Hu, Huimin Zhang, Sifei Han. The lymphatic system plays a major role in the absorption of subcutaneously administered trastuzumab in a lymph-duct cannulated rat model [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 4342.