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Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats

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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 duct-cannulated 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 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.

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Acknowledgments

The authors would like to thank Dr. John Harrold for development and continuous support of the Ubiquity modeling framework. The study was supported in part by a grant from Bristol Myers Squibb to Leonid Kagan.

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Xizhe Gao, Sarah Oh & Leonid Kagan

  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

    Xizhe Gao & Leonid Kagan

  3. Comparative Medicine Resources, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Gregory Voronin & Raymond Rosa

  4. Nonclinical Research and Development, Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, 08648, USA

    Claudia Generaux & Anne Rose

  5. Nonclinical Research and Development, Nonclinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, NJ, 08648, USA

    Alexander Kozhich & Gerard Dalglish

Authors
  1. Xizhe Gao
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  2. Gregory Voronin
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  3. Claudia Generaux
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  4. Anne Rose
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  5. Alexander Kozhich
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  6. Gerard Dalglish
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  7. Raymond Rosa
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  8. Sarah Oh
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  9. Leonid Kagan
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Correspondence to Leonid Kagan.

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Gao, X., Voronin, G., Generaux, C. et al. Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats. Pharm Res 37, 155 (2020). https://doi.org/10.1007/s11095-020-02860-6

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  • DOI: https://doi.org/10.1007/s11095-020-02860-6

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