3041 Background: Bevacizumab (BV) is an IgG1 monoclonal antibody that inhibits all isoforms of VEGF-A. The addition of BV to irinotecan/5-FU/LV (bIFL) in patients with metastatic colorectal carcinoma resulted in a 34% reduction in the risk of death, as compared to bIFL alone (p=0.00004), and in a median survival increase from 15.6 to 20.3 months (Hurwitz, ASCO 2003). Due to its long elimination half-life, BV was administered every 2 or 3 weeks in Phase II and III clinical trials. This analysis further characterizes the impact of dosing schedules on BV exposure. Methods: A retrospective non-compartmental analysis was conducted to compare several measures of drug exposure, using observed data from 2 Phase II dose-ranging trials (1 study in colorectal carcinoma (AVF0780g) and 1 in non small cell carcinoma (AVF0757g)), where BV was administered at doses of 5 and 7.5 mg/kg every 2 or 3 weeks, respectively. Simulations (500 subjects) were also performed to compare drug exposure for different administration frequencies, using a 2-compartment population PK model that was recently developed based on data from 491 subjects from 8 clinical trials. Results: Observed and simulated steady-state concentrations following BV dosing at 2.5 mg/kg/week every 2 or 3 weeks, are presented in the table below: Conclusions: Administration of BV at 2.5 mg/kg/week every 2 or 3 weeks results in similar overall exposure, due to its slow clearance and long elimination half-life of 20 days. Thus, the frequency of BV administration can easily be coordinated with the schedule of administration of the cytotoxic agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech Inc.

BV, a recombinant humanized IgG1 monoclonal antibody against vascular endothelial growth factor (VEGF) was demonstrated to improve survival in previously untreated metastatic colorectal cancer when added to standard chemotherapy. Pooled data (total 4629 BV concentration from 491 subjects) from 8 Phase I to Phase III clinical trials were analyzed using NONMEM and a two-compartment structural model. Body weight and gender were the most significant covariates for both CL and Vc. The change in BV CL for extreme body weights (49 and 114 kg) was 30% around the typical value. After adjusting the weight, men had a 26% faster CL than females. In the final model, CL and Vc were 0.207 L/day and 2.66 L, respectively for the typical (female) patient. The inter-patient variability (%CV) in CL and Vc was 26% and 17%, respectively. BV terminal half-life was 19.9 and 19.3 days for a typical male and female patient. Low albumin and high alkaline phosphatase serum concentrations were associated with a faster CL (+19% and 23%, respectively). Concomitant administration of the combination irinotecan/5-fluorouracil in patients with colon cancer did not influence BV CL. The effect of various dosing regimen on bevacizumab exposure will be explored using simulations. Clinical Pharmacology & Therapeutics (2004) 75, P91–P91; doi: 10.1016/j.clpt.2003.11.347