Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.
OBJECTIVE
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.


CONCLUSIONS
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.
Radwanski
E
E
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
Chakraborty
A
A
Van Wart
S
S
Huhn
R D
RD
Cutler
D L
DL
Affrime
M B
MB
Jusko
W J
WJ
D018592:Cross-Over Studies; D006801:Humans; D007165:Immunosuppression Therapy; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10