Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients

Abstract

Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy.

Experimental design: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters.

Results: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity.

Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.

FIG. 1.

The immediate anterior and posterior whole-body scan images after IP ²¹²Pb-TCMC-trastuzumab (left) are compared with the repeat scan the next day. ^99mTc marker at the right shoulder (arrow) plus the ²¹²Pb standard adjacent to the right ankle provide anatomic locations outside the abdominal area as does the transmission scan (right) that displays body anatomy.

FIG. 2.

Data points represent mean exposure rate of radioactivity at 4 time points in the initial 24 hours after IP ²¹²Pb-TCMC-trastuzumab. Measurements over the abdomen are compared with those at the chest, axilla, and femur. The actual data points (mean±one standard deviation) are shown along with theoretical curves of physical radioactive decay. There was no adjustment for urinary excretion of radioactivity.