D. Cronier (1); D. B. Radtke (2); S. P. Carpenter (3); J. E. Wooldridge (2)
(1) Eli Lilly and Company, Windlesham, Surrey, UK; (2) Eli Lilly and Comany, Indianapolis, IN, USA.; (3) Applied Molecular Evolution, San Diego, CA, USA
Objectives: AME-133v is a humanized monoclonal antibody that was engineered ti have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab in vitro. The safety, pharmacokinetics (PK) and preliminary efficacy of AME-133v were assessed in a phase 1/2 clinical trial in patients with previously treated follicular lymphoma (FL). The objective of this study is to characterize the PK of AME-133v in the target patient population.
Methods: 5 dose levels of AME-133v (2, 7.5, 30, 100 and 375 mg/m2) were tested in a total of 67 patients with previously treated CD20+ FL. AME-133v was administered intravenously in 4 weekly infusions. Blood samples were obtained pre-dose and 1, 3-5 days after infusion 1, pre-dose and post-dose during infusions 2, 3 and 4, and 1, 5, and 9 weeks after infusion 4. The PK database (399 data points) was analyzed by nonlinear mixed-effect modeling (NONMEM). Covariates including demographic characteristics and the FCyRIIa receptor genotype were evaluated fir their influence on the population PK parmaters of AME-133v.
Results: Owing to serum concentrations falling below the limit of detection, the 2 mg/m2 dose group was not included in the analysis. The basic model selected was a 2-compartment pharmacokinetic model with first-order elimination. However, a different typical CL value had to be estimated for each dose group. The typical values for V1, Q and V2 were 2.99 L, 0.94 L/day and 3.31 L, respectively. the typical CL value was 0.70, 0.53, 0.26 and 0.27 L/day for 7.5, 30, 100 and 375 mg/m2, respectively, which indicates a linearization of the elimination rate of AME-133v at doses of 100 mg/m2 and above. Inter-individual variability was moderate to high with CVs of 45.9, 34.1 and 50.0% for CL, V1 and V2, respectively. The only covariate found to influence the PK of AME-133v was BSA which explained 9.6% of the variability on V1. The form of the FcyRIIIa receptor did was not found to have a significant effect on the PK of AME-133v/
Conclusions: The PK of AME-133v were best described by a 2-compartment model. Clearance was found to be dose-dependent with a linearization of the elimination rate at doses of 100 mg/m2 and above. BSA has a statistically significant influence on V1 whereas the FcyRIIIa genotype does not seem to influence the disposition of AME-133v.
Reference: PAGE 21 (2012) Abstr 2382 [www.page-meeting.org/?abstract=2382]
Poster: Oncology