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Concomitant Administration of Bevacizumab, Irinotecan, 5-Fluorouracil, and Leucovorin: Nonclinical Safety and Pharmacokinetics

Departments of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, USA

Ann Bricarello

Study Management Group, Genentech Inc., South San Francisco, California, USA

Brian J. Christian

Covance Laboratories, Madison, Wisconsin, USA

Christina L. Zuch
Barbara Mounho

Department of Safety Assessment, Genentech Inc., South San Francisco, California, USA

Correspondence: Address correspondence to Christina Zuch de Zafra, Genentech Inc., Mailstop 86, 1 DNA Way, South San Francisco, CA 94080, USA. E-mail:czuch{at}gene.com

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 (t_1/2 = 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.

Key Words: Avastin • Bevacizumab • Cynomolgus Monkey • Monoclonal Antibody • Saltz Regimen

International Journal of Toxicology, Vol. 24, No. 5, 357-363 (2005)
DOI: 10.1080/10915810500209353


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