Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers

Objective: The pharmacoimmunodynamic interactions of recombinant human inte rleukin-10 and prednisolone were examined in 12 normal male volunteers. Methods: Single doses of interleukin-10 (8 mu g/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic p arameters. Response measurements included whole blood lipopolysaccharide-st imulated cytokine (tumor necrosis factor-alpha, interleukin-1 beta) product ion, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, an d differential white blood cell counts (including monocytes, lymphocytes, a nd neutrophils), Extended indirect-response models were used to deal with d iverse drug interactions in assessing single and joint effects of interleuk in-10 and prednisolone, Results: NO pharmacokinetic alterations in interleukin-l0 or prednisolone w ere found, Dosing with, interleukin-l0 produced strong inhibition of ex viv o cytokine production for the 24-hour postdosing period, whereas prednisolo ne, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte prolifera tion for 6 hours, whereas interleukin-l0 failed to alter this measure, Thei r joint effects on these responses were inhibitory consonant with the stron ger agent. Marked changes in various leukocyte kinetics occurred. The stero id caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 Or SC 50 values of 10 to 20 ng/mL, Interleukin-10 elevated monocytes and neutroph ils and lowered lymphocyte counts, with IC50 or SC50 Values of 0.7 to 1.3 n g/mL, Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, wi th neutrophils exhibiting greater changes in net response. Conclusion: Interleukin-10 and prednisolone interacted favorably for the me asured pharmacoimmunodynamic indices with no kinetic alterations but net re sponses that were similar to or greater than effects produced by the more s trongly acting agent.