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    The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein. Etanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days. Model-based SC bioavailability of etanercept was 65.2% in the control group. In lymph-cannulated rats, etanercept concentration in the lymph was consistently lower than in serum following IV dosing; and the concentration in the lymph was significantly higher than in serum after SC injection. The absorption occurred predominantly through the lymphatic pathway (82.7%), and only 17.3% by direct uptake into the central compartment (blood pathway). Lymphatic cannulation reduced the area under the serum concentration-time curve by 28% in IV group and by 91% in SC group. A mechanistic pharmacokinetic model that combined dual absorption pathways with redistribution of the systemically available protein drug into lymph was developed. The model successfully captured serum and lymph data in all groups simultaneously, and all parameters were estimated with sufficient precision. Lymphatic system was shown to play an essential role in systemic disposition and SC absorption of etanercept.


    Xizhe Gao, Gregory Voronin, Claudia Generaux, Anne Rose, Alexander Kozhich, Gerard Dalglish, Raymond Rosa, Sarah Oh, Leonid Kagan. Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats. Pharmaceutical research. 2020 Jul 27;37(8):155

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    PMID: 32720159

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