Pharmacokinetics of radiolabeled polyclonal antiferritin in patients with Hodgkin's disease.

Abstract

The objective was to identify pharmacokinetic parameters predictive for tumor response and normal tissue side effects after i.v. administered radiolabeled rabbit antihuman ferritin IgG. Twenty-eight patients with recurrent Hodgkin's disease received 2 mg of rabbit antihuman ferritin i.v., labeled with 4-7 mCi of In-111 followed by two doses of 0.25, one dose of 0.3, or one dose of 0.4 mCi of Y-90-labeled antiferritin per kg of body weight 1 week later. Radioactivity and HPLC measurements of blood and urine samples and liver and tumor volumes identified on sequential whole-body scans provided the data for a pharmacokinetic analysis covering the first 6 days after the administration of the radioimmunoconjugate. Side effects and tumor response were recorded. Temporary hematological toxicity was noted in all patients. Sixteen patients showed a tumor response. The Y-90 blood level at 1 h after administration correlated with the severity of subsequent hematological toxicity. The rapid blood elimination half-life of radioactivity was 4.4 h. Less than 5% of the administered radioactivity was eliminated in the first 24 h urine. The slow blood elimination half-life was 44 and 37 h for In-111 and Y-90, respectively. One of 12 retreated patients produced anti-rabbit IgG antibodies. The volume of distribution was larger for Y-90 than for In-111-labeled antiferritin (160 versus 110% of estimated blood volume). Accidentally extravasated rabbit IgG was rapidly catabolized in perivascular tissues with an effective half-life of less than 35 h. Slower catabolism was noted for rabbit IgG in blood (t(1/2) = 40 h), liver (t(1/2) = 62 h) or tumor (t(1/2) = 40-80 h). Twelve of 13 patients with an effective tumor half-life > 57 h showed a tumor response. I.v. administered polyclonal rabbit antihuman ferritin, labeled with In-111 or Y-90 is stable in vivo and targets Hodgkin's disease. Intravascular Y-90 causes a vascular leak and a larger volume of distribution for antiferritin. Elevated Y-90 blood levels at 1 h and a tumor half-life of >57 h predict for hematological toxicity and tumor response, respectively.