Mechanism of Action
Possible mechanisms of action of the BEXXAR therapeutic regimen include induction of apoptosis (Ref. 5), complement-dependent cytotoxicity (CDC) (Ref. 6), and antibody-dependent cellular cytotoxicity (ADCC) (Ref. 5) mediated by the antibody. Additionally, cell death is associated with ionizing radiation from the radioisotope.

Pharmacokinetics/Pharmacodynamics
The phase 1 study of Iodine I 131 Tositumomab determined that a 475 mg predose of unlabeled antibody decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. The median blood clearance following administration of 485 mg of Tositumomab in 110 patients with NHL was 68.2 mg/hr (range: 30.2−260.8 mg/hr). Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have a faster clearance, shorter terminal half-life, and larger volume of distribution. The total body clearance, as measured by total body gamma camera counts, was dependent on the same factors noted for blood clearance. Patient-specific dosing, based on total body clearance, provided a consistent radiation dose, despite variable pharmacokinetics, by allowing each patient’s administered activity to be adjusted for individual patient variables. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with NHL was 67 hours (range: 28-115 hours).

Elimination of Iodine-131 occurs by decay (see Table 2) and excretion in the urine. Urine was collected for 49 dosimetric doses. After 5 days, the whole body clearance was 67% of the injected dose. Ninety-eight percent of the clearance was accounted for in the urine.

Administration of the BEXXAR therapeutic regimen results in sustained depletion of circulating CD20 positive cells. The impact of administration of the BEXXAR therapeutic regimen on circulating CD20 positive cells was assessed in two clinical studies, one conducted in chemotherapy naïve patients and one in heavily pretreated patients. The assessment of circulating lymphocytes did not distinguish normal from malignant cells. Consequently, assessment of recovery of normal B cell function was not directly assessed. At seven weeks, the median number of circulating CD20 positive cells was zero (range: 0-490 cells/mm3). Lymphocyte recovery began at approximately 12 weeks following treatment. Among patients who had CD20 positive cell counts recorded at baseline and at 6 months, 8 of 58 (14%) chemotherapy naïve patients had CD20 positive cell counts below normal limits at six months and 6 of 19 (32%) heavily pretreated patients had CD20 positive cell counts below normal limits at six months. There was no consistent effect of the BEXXAR therapeutic regimen on post-treatment serum IgG, IgA, or IgM levels.

Radiation Dosimetry
Estimations of radiation-absorbed doses for Iodine I 131 Tositumomab were performed using sequential whole body images and the MIRDOSE 3 software program. Patients with apparent thyroid, stomach,