Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats.

Abstract

The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein. Etanercept 1mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoraciclymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6days. Model-based SC bioavailability of etanercept was 65.2% in thecontrol 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 serumconcentration-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.