Population Pharmacokinetics (Pk) Of Tremelimumab In Patients (Pts) With Melanoma

3048 Background: Tremelimumab is a fully human monoclonal antibody targeted against CTLA4, a protein on T cells critical for regulating T-cell activities, which is under development for treatment of various cancers, including melanoma. Population PK analysis was conducted using concentration-time data from 450 pts, most with melanoma or solid tumors, enrolled in four phase I or II studies that evaluated PK, tolerability, and efficacy of single-agent tremelimumab. Methods: Tremelimumab was administered intravenously either as single dose or multiple doses every 4 or 12 weeks; doses varied between 0.01 and 15 mg/kg. PK was determined using nonlinear mixed-effect modeling implemented in NONMEM VI. Baseline characteristics, including body weight, ECOG score, age, sex, serum creatinine, AST, ALT, and bilirubin, and formulation effects were investigated as potential factors affecting PK. Tremelimumab plasma concentrations were determined using a sensitive, specific, validated ELISA assay. Results: A two-compartment linear model adequately described tremelimumab concentration-time data; an additive residual error model was employed on log-transformed data. Initial and terminal half-lives were 2.5 days and 22 days, respectively. Estimated parameter values were: 0.0109 L/hr for CL (clearance), 3.72 L for V1 (central volume of distribution), 0.0172 L/hr for Q (intercompartment clearance), and 3.31 L for V2 (peripheral volume of distribution). Females had 29.6% smaller V2 compared with males. Both CL and central V1 increased with weight. An ECOG score of ≥1 showed 20.2% increase in CL compared with a score of 0. New commercial formulation decreased CL by 18.5%. The model-predicted area under concentration-time curve value in females was 13.3% greater than males (p=0.5). None of the other covariates tested significantly affected PK. Furthermore, tremelimumab was tolerated in most pts at all doses tested. Conclusions: PK of tremelimumab were shown to be affected by weight, baseline ECOG score, and formulation. However, no effects other than weight were considered clinically significant enough to warrant treatment regimen change. Further investigation of PK-response relationships is warranted. [Table: see text]