g/kg every 2 weeks plus placebo and 51 to Avastin 10 mg/kg every 2 weeks plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the Avastin + Placebo arm and the Avastin + Erlotinib arm (median PFS 8.5 versus 9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib to bevacizumab did not result in an improvement in OS (HR = 1.764; p=0.1789), duration of objective response (6.7 vs 9.1 months) or time to symptom progression (HR = 1.172; p = 0.5076).
AVF0890
This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab versus placebo. A total of 116 patients were randomized to receive bevacizumab 3 mg/kg every 2 weeks (n=39), 10 mg/kg every 2 weeks; (n=37), or placebo (n=40). An interim analysis showed there was a significant prolongation of the time to progression of disease in the 10 mg/kg group as compared with the placebo group (hazard ratio, 2.55; p<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the 3 mg/kg group and that in the placebo group (hazard ratio, 1.26; p=0.053). Four patients had objective (partial) response, and all of these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies, in all subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, lung carcinoma (small cell and non-small cell carcinoma) and kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney).
5.2 Pharmacokinetic properties
The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.
Distribution
The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male patients respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients respectively, when bevacizumab is coadministered with anti-neoaplastic agents. After correcting for body weight, male patients had a larger Vc (+ 20%) than female patients.
Metabolism
Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgG molecule which does not bind VEGF. The metabolism and elimination of bevacizumab is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRn receptor result in protection from cellular metabolism and the long terminal half-life.
Elimination
The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, respectively. After correcting for body weight, male patients had a higher bevacizumab clearance (+ 17%) than females. According to the tw
