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Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10

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Abstract

Purpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing.

Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr.

Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration.

Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

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Authors and Affiliations

  1. Schering-Plough Research Institute, Kenilworth, New Jersey, 07033-0539

    Elaine Radwanski, Scott Van Wart, David L. Cutler & Melton B. Affrime

  2. University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, 08903-0019

    Abhijit Chakraborty & Richard D. Huhn

  3. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York, 14260

    William J. Jusko

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  1. Elaine Radwanski
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  2. Abhijit Chakraborty
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  3. Scott Van Wart
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  4. Richard D. Huhn
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  5. David L. Cutler
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  6. Melton B. Affrime
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  7. William J. Jusko
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Radwanski, E., Chakraborty, A., Van Wart, S. et al. Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10. Pharm Res 15, 1895–1901 (1998). https://doi.org/10.1023/A:1011918425629

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