Pharmacokinetics and leukocyte responses of recombinant human interleukin-10

Purpose, To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHulL-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 mu g/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-alpha and IL-1 beta) 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, V-ss 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-alpha and IL-1 beta 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 I-max values were about 0.85 for both TNF-alpha and IL-1 beta 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 the SC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.