Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.

Autor: Radwanski E; Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA., Chakraborty A, Van Wart S, Huhn RD, Cutler DL, Affrime MB, Jusko WJ
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 1998 Dec; Vol. 15 (12), pp. 1895-901.
DOI: 10.1023/a:1011918425629
Abstrakt: Purpose: To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing.
Methods: A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. 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-alpha and IL-1beta) 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 (s.c. and i.v.). The i.v. 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 s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta 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 i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration.
Conclusion: rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.
Databáze: MEDLINE
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