title: Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics.
abstract: Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.
authors.affiliation: Department of Pharmacokinetic Sciences, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Gaudreault
authors.forename: Vanessa
authors.initials: V
authors.lastname: Shiu
authors.forename: Ann
authors.initials: A
authors.lastname: Bricarello
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Christian
authors.forename: Christina L
authors.initials: CL
authors.lastname: Zuch
authors.forename: Barbara
authors.initials: B
authors.lastname: Mounho
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006207:Half-Life; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D011355:Prodrugs; D011897:Random Allocation
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011355:Prodrugs; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin