title: Lower exposure and faster clearance of bevacizumab in gastric cancer and the impact of patient variables: analysis of individual data from AVAGAST phase III trial.
abstract: Altered pharmacokinetics of antibody drugs has been reported in advanced gastric cancer (AGC). We aim to evaluate bevacizumab pharmacokinetics in AGC from the Phase III trial (AVAGAST), and explore the influence of patient variables. Bevacizumab concentrations (Cp) were measured in plasma samples taken following disease progression from 162 patients (7.5 mg/kg every 3 weeks). Predicted Cp [median and 90% prediction interval] was simulated using the population pharmacokinetic model established for other cancers (PPK model) and compared to observed Cp. Bevacizumab clearance was estimated using NONMEM and compared between subgroups. Patient characteristics of AGC are similar to other cancers except for lower body weight despite higher percentage of males. Eighty-five percent of observed Cp was below the median predicted Cp and 38% below the lower boundary of the 90% prediction interval. Median bevacizumab clearance in AGC was 4.5 versus 3 mL/day/kg in other cancers. Bevacizumab clearance was significantly faster (p < 0.05) in patients without gastrectomy (n = 42) or lower albumin. Clearance appeared to be faster in patients with lower total protein, higher ECOG scores, more metastatic sites, and poorer response. No significant difference in bevacizumab concentrations and clearance was observed between Asian and Non-Asian patients. AGC patients exhibited significantly lower bevacizumab exposure due to an approximate 50% increase in clearance versus other cancers. Bevacizumab is cleared faster in patients without prior gastrectomy. No significant difference in bevacizumab pharmacokinetics was observed between Asian and Non-Asian patients. The underlying mechanism for faster bevacizumab clearance in AGC is unknown and warrants further research.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA, han.kelong@gene.com.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.forename: John
authors.initials: J
authors.lastname: Lowe
authors.forename: Martina A
authors.initials: MA
authors.lastname: Sersch
authors.forename: David E
authors.initials: DE
authors.lastname: Allison
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D000068258:Bevacizumab; D001682:Biological Availability; D000069287:Capecitabine; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D016903:Drug Monitoring; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005743:Gastrectomy; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil