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Subcutaneous Absorption of Monoclonal Antibodies: Role of Dose, Site of Injection, and Injection Volume on Rituximab Pharmacokinetics in Rats

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ABSTRACT

Purpose

To determine the effect of dose, the anatomical site of injection, and the injection volume on subcutaneous absorption of rituximab in rats and to explore absorption mechanisms using pharmacokinetic modeling.

Methods

Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back, abdomen, and foot of rats. Several pharmacokinetic models were developed that included linear and saturable absorption, and degradation and/or protective binding at the injection site.

Results

Rituximab exhibited linear kinetics following intravenous administration; however, bioavailability following subcutaneous injection was inversely related to the dose level. For the 1 mg/kg dose, bioavailability was approximately 70% at all tested injection sites, with faster absorption from the foot (Tmax = 12 h for foot vs. 4.6 days for back). Bioavailability for the 10 mg/kg dose was 44 and 31% for the abdomen and back sites and 18% for 40 mg/kg injected at the back. A pharmacokinetic model that included binding as part of the absorption mechanism successfully captured the nonlinearities in rituximab absorption.

Conclusion

The anatomical site of subcutaneous injection influences the rate of absorption and bioavailability of rituximab in rats. Saturable binding may be a major determinant of the nonlinear absorptive transport of monoclonal antibodies.

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ACKNOWLEDGMENTS & DISCLOSURES

We thank Dr. John M. Harrold for his help in developing the MATLAB code for this project. Partial results of this study were presented at the 12th Buffalo Pharmaceutics Symposium in Buffalo, NY. This work was supported by the Center for Protein Therapeutics, University at Buffalo, SUNY.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 363 Hochstetter Hall, Buffalo, New York, 14260, USA

    Leonid Kagan

  2. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA

    Michael R. Turner, Sathy V. Balu-Iyer & Donald E. Mager

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  1. Leonid Kagan
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  2. Michael R. Turner
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  3. Sathy V. Balu-Iyer
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  4. Donald E. Mager
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Correspondence to Leonid Kagan.

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Kagan, L., Turner, M.R., Balu-Iyer, S.V. et al. Subcutaneous Absorption of Monoclonal Antibodies: Role of Dose, Site of Injection, and Injection Volume on Rituximab Pharmacokinetics in Rats. Pharm Res 29, 490–499 (2012). https://doi.org/10.1007/s11095-011-0578-3

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