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Pharmacokinetics and safety of bevacizumab administered in combination with cisplatin and paclitaxel in cynomolgus monkeys

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Abstract

Purpose

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 μg/ml × day, respectively. AUC0-t values for paclitaxel with or without concomitantly administered bevacizumab were 10.9 ± 2.9 and 10.3 ± 3.7 μg/ml × 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.

Conclusion

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.

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Author information

Author notes

  1. Yvonne S. Lin

    Present address: Department of Pharmaceutics, University of Washington, Seattle, WA, 98195, USA

  2. Nishit B. Modi

    Present address: ALZA Corporation, 1900 Charleston Road, Mountain View, CA, 94039, USA

Authors and Affiliations

  1. Department of Pharmacokinetic, Pharmacodynamic and Bioanalytical Sciences, Genentech Inc., 1 DNA Way (MS-70), South San Francisco, CA, 94080, USA

    Lu Xu, Yvonne S. Lin, Nishit B. Modi & Bert L. Lum

  2. Department of Safety Assessment, Genentech Inc., South San Francisco, CA, 94080, USA

    Christina L. Zuch

Authors
  1. Lu Xu
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  2. Christina L. Zuch
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  5. Bert L. Lum
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Correspondence to Bert L. Lum.

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Xu, L., Zuch, C.L., Lin, Y.S. et al. Pharmacokinetics and safety of bevacizumab administered in combination with cisplatin and paclitaxel in cynomolgus monkeys. Cancer Chemother Pharmacol 61, 607–614 (2008). https://doi.org/10.1007/s00280-007-0513-9

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  • DOI: https://doi.org/10.1007/s00280-007-0513-9

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