Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma

9576 Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) that significantly improves survival in high-risk neuroblastoma, was previously reported to be highly variable in children, and its clearance (CL, 130 mL/h · m2) and volume of distribution (Vdss, 32 L/m2) were >10-fold higher than the CL and Vdss of other cMoAbs. Characterizing the PK of ch14.18 and the factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Detailed PK sampling was performed prior to, during and for 25 d after 4 daily 10 h infusions of 25 mg/m2 of ch14.18 administered with sargramostim (ANBL0032) in children enrolled on an IRB-approved institutional correlative protocol supported by United Therapeutics Corp. Ch14.18 concentrations were measured with a validated ELISA with a lower limit of detection of 0.44 mcg/mL. PK parameters were derived using non-compartmental methods and reported as median (range). Results: 5 males and 4 females, median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were re-studied on C3. Data from 3 patients are not included because pre-treatment plasma samples contained a substance that interfered with the ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 (120-390) h, and the CL was 11 (3.8-16) mL/h · m2, which is similar to the average CL of 4 other cMoAbs (11 mL/h · m2). The Vdss of 2.8 (1.2-3.9) L/m2 approximated blood volume and was similar to the Vdss of other cMoAbs (1.7 L/m2) and humanized MoAbs (2.8 L/m2). AUC0-∞ in 2 patients studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children are similar to those in adults receiving ch14.18 at the same dose and similar to other cMoAbs. Ch14.18 PK in children was less variable than previously reported. The identity of the interfering substance in the plasma of some patients requires further investigation. A limited sampling strategy will be developed from these data for use in larger multi-institutional PK studies of ch14.18.