Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

• Published in: Biopharmaceutics & drug disposition Vol. 36; no. 2; pp. 115 - 125
• Main Authors: Fathallah, Anas M., Turner, Michael R., Mager, Donald E., Balu-Iyer, Sathy V.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2015; Wiley Subscription Services, Inc
• Subjects: Animals; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Antibodies, Monoclonal, Murine-Derived - blood; Antibodies, Monoclonal, Murine-Derived - pharmacokinetics; Biological Availability; biologics; Buffers; Hypertonic Solutions - pharmacology; Injections, Subcutaneous; Lymph Nodes - drug effects; Lymph Nodes - metabolism; lymphatic uptake; Male; mannitol; Mannitol - pharmacology; Mice; O-phospho-L-serine (OPLS); osmolarity; Phosphoserine - pharmacology; Rituximab; Sodium Chloride - pharmacology; Tromethamine - pharmacology; lymphatic uptake; O-phospho-L-serine (OPLS); biologics; mannitol; osmolarity
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.1925

The subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after s.c. administration remains a major challenge. In this work we investigated the effects of excipient dependent hyperosmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as the animal model, we compared the effects of NaCl, mannitol and O‐phospho‐L‐serine (OPLS) on the plasma concentration of rituximab over 5 days after s.c. administration. An increase was observed in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, compared with isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to the improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph nodes in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatics, as estimated by the model, increased from 0.05% in isotonic buffer to 13% in hypertonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. The data suggest that hypertonic solutions may be a viable option for improving s.c. bioavailability. Copyright © 2014 John Wiley & Sons, Ltd.