Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats
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RESEARCH PAPER
Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats Xizhe Gao 1,2 & Gregory Voronin 3 & Claudia Generaux 4 & Anne Rose 4 & Alexander Kozhich 5 & Gerard Dalglish 5 & Raymond Rosa 3 & Sarah Oh 1 & Leonid Kagan 1,2
Received: 12 May 2020 / Accepted: 15 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein. Methods Etanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph ductcannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days. Results 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
* Leonid Kagan [email protected] 1
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
2
Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
3
Comparative Medicine Resources, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
4
Nonclinical Research and Development, Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ 08648, USA
5
Nonclinical Research and Development, Nonclinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, NJ 08648, USA
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. Conclusions Lymphatic system was shown to play an essential role in systemic disposition and SC absorption of etanercept.
KEYWORDS Biologics . Protein therapeutics . Biotherapeutics . Modeling and simulation . PK modeling . Lymphatic drug absorption
INTRODUCTION Approximately 24% of new drugs approved by the U.S. Food and Drug Administration (FDA) from 2010 to 2017 are biologics (1). In 2016, the global protein therapeutics market was valued at $140 billion. The projected market cap will be $218 billion by 2023, and antibody-based fusion protein is one of the most rapidly growing segments (2). Protein therapeutics are mainly delivered by intravenous (IV) an
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