The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats

• Published in: Molecular pharmaceutics 2014-02, Vol.11 (2), p.496-504
• Main Authors: Dahlberg, Annette M, Kaminskas, Lisa M, Smith, Alanna, Nicolazzo, Joseph A, Porter, Christopher J. H, Bulitta, Jürgen B, McIntosh, Michelle P
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Injections, Subcutaneous; Lymphatic System - metabolism; Rats; Rats, Sprague-Dawley; Trastuzumab
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp400464s

Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly understood. This study was conducted to develop a better understanding of the mechanisms governing the subcutaneous absorption and trafficking of monoclonal antibodies. Specifically, the role of the lymphatic system in the absorption and prolonged plasma exposure of trastuzumab was explored in thoracic lymph duct-cannulated rats after SC and IV dosing. A population pharmacokinetic model was developed in S-ADAPT to simultaneously fit all plasma and lymph concentrations and to predict the pharmacokinetics in nonlymph duct-cannulated animals. The estimated absolute bioavailability of trastuzumab after SC administration in rats was 85.5%. Following SC administration, 53.1% of the trastuzumab dose was absorbed via a first-order process (mean absorption time: 99.6 h) into the peripheral lymph compartment and 32.4% of the dose was absorbed by a Michaelis–Menten process into the central compartment. Recovery in thoracic lymph over 30 h was 26.7% after SC and 44.1% after IV administration. This study highlights for the first time the significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab, with the model predicting an extensive distribution of this monoclonal antibody into the lymph following SC and IV administration. This extensive direct absorption from the SC injection site into lymph may enable novel therapeutic strategies for the treatment of lymph resident metastatic cancer.