Immunological response to repeated administration of recombinant human erythropoietin in rats: biphasic effect on its pharmacokinetics.

We studied changes in the pharmacokinetics of 125I-recombinant human erythropoietin (125I-rh-EPO) after repeated subcutaneous administration once a week for 4 weeks. The plasma level of trichloroacetic acid-precipitable radioactivity after the fourth administration of 125I-rh-EPO was minimal in 8 of 10 rats, whereas in the other two rats, the plasma level was almost the same or somewhat higher than that in control rats that had received the vehicle solution 3 times instead of the first three sequential administrations. Antibody against rh-EPO in serum was detected in all 10 rats receiving multiple administrations of 125I-rh-EPO. However, the binding capacity for 125I-rh-EPO in the latter two rats, assessed by an in vitro serum binding study, was lower than for the other eight rats, suggesting that the antibody level in these two was lower. The effect of intravenous preinjection of various volumes of anti-rh-EPO antiserum on the pharmacokinetics of 125I-rh-EPO was examined. The half-life in the beta-phase was prolonged at lower doses of antiserum. When the pretreatment dose of antiserum was further increased, the half-life in the beta-phase rather shortened and the total body clearance (CL(total) increased. These results suggest that repeated administration of rh-EPO induces the production of antibody against rh-EPO that affects the pharmacokinetics of rh-EPO in a biphasic manner; CL(total) was reduced when a small amount of antibody was produced, and CL(total) was increased when a large amount of antibody was produced.