Pharmacokinetics and safety of bevacizumab administered in combination with cisplatin and paclitaxel in cynomolgus monkeys.
OBJECTIVE
Bevacizumab is the first anti-angiogenic monoclonal antibody approved for use in combination with chemotherapy for treatment of a variety of solid tumors. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with paclitaxel and cisplatin to cynomolgus monkeys, and to assess the pharmacokinetic and safety interactions between bevacizumab and the two chemotherapeutic agents.


METHODS
Twenty male cynomolgus monkeys (Macaca fasicularis) were randomized to one of four treatment groups: vehicle, bevacizumab alone, cisplatin alone, and the combination of cisplatin and bevacizumab. Blood collection over serial time points allowed determination of the pharmacokinetic parameters of paclitaxel and bevacizumab and the maximum concentration (C (max)) for cisplatin. Drug concentrations were determined by graphite-furnace atomic absorption, high performance liquid chromatography, and enzyme-linked immunosorbent assay methods, for cisplatin, paclitaxel, and bevacizumab, respectively.


RESULTS
AUC0-t values for bevacizumab when administered alone or in combination with chemotherapy were 6,747 +/- 1,872 and 7,366 +/- 1,599 microg/ml x day, respectively. AUC0-t values for paclitaxel with or without concomitantly administered bevacizumab were 10.9 +/- 2.9 and 10.3 +/- 3.7 microg/ml x day, respectively. No alterations in the C (max) of bevacizumab, paclitaxel, or cisplatin were observed between any of the treatment groups. As expected, based on their known safety profile, the administration of cisplatin and paclitaxel were associated with vomiting, decreased body weight, and transient decreases in white blood cell and absolute neutrophil counts; concomitant bevacizumab administration did not alter the incidence or severity of these toxicological effects.


CONCLUSIONS
Pharmacokinetic estimates for bevacizumab, paclitaxel and cisplatin indicate that combination of bevacizumab with the two chemotherapeutic agents does not result in a pharmacokinetic interaction. Moreover, the addition of bevacizumab to the chemotherapy regimen did not appear to alter the safety profiles of cisplatin/paclitaxel in cynomolgus monkeys. Results from the present study supported the clinical development of bevacizumab treatment regimens in combination with the chemotherapeutic agents paclitaxel and cisplatin.
Xu
Lu
L
Department of Pharmacokinetic, Pharmacodynamic and Bioanalytical Sciences, Genentech Inc., 1 DNA Way (MS-70), South San Francisco, CA, 94080, USA.
Zuch
Christina L
CL
Lin
Yvonne S
YS
Modi
Nishit B
NB
Lum
Bert L
BL
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D000068258:Bevacizumab; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000068258:Bevacizumab; D017239:Paclitaxel; D002945:Cisplatin