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Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

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Abstract

Purpose

The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.

Methods

This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.

Results

Forty-five subjects were enrolled. No difference in dose-normalized AUC0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.

Conclusion

Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.

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Acknowledgments

We are grateful to Jacques Gaudreault and Dan Spyker for their useful input and insights into the study design. This study was supported by Genentech and Cancer Center Support Grant NCI-P30 CA 006927 to Fox Chase Cancer Center.

Conflict of interest statement

Lu Xu receives remuneration and stock ownership from Genentech. Coen Bernaards receives remuneration and stock ownership from Genentech. Andrew Dorr has a consultant/advisory role with Genentech. Julie Hambleton receives remuneration and stock ownership from Genentech. Scott Holden receives remuneration and stock ownership from Genentech. Anne Kearns receives remuneration and stock ownership from Genentech. Bert Lum receives remuneration and stock ownership from Genentech. Neal J. Meropol has a consultant/advisory role with and receives funding from Genentech. Peter J. O’Dwyer receives funding from Genentech. Crystal Denlinger, Rebecca Blanchard, Samuel Litwin, Cynthia Spittle, Daniel J. Berg, Susan McLaughlin, Maryann Redlinger, Sara Kenkare-Mitra have declared no conflict of interest.

Author information

Author notes

  1. Rebecca Blanchard

    Present address: Merck Pharmaceuticals, Whitehouse Station, Rahway, NJ, USA

Authors and Affiliations

  1. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Crystal S. Denlinger, Rebecca Blanchard, Samuel Litwin, Cynthia Spittle, Susan McLaughlin & Neal J. Meropol

  2. University of Pennsylvania, Philadelphia, PA, USA

    Maryann Redlinger & Peter J. O’Dwyer

  3. University of Iowa, Iowa City, IA, USA

    Daniel J. Berg

  4. Genentech, Inc., South San Francisco, CA, USA

    Lu Xu, Coen Bernaards, Andrew Dorr, Julie Hambleton, Scott Holden, Anne Kearns, Sara Kenkare-Mitra & Bert Lum

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  1. Crystal S. Denlinger
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Corresponding author

Correspondence to Neal J. Meropol.

Additional information

N. J. Meropol and P. J. O’Dwyer contributed equally to this work.

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Denlinger, C.S., Blanchard, R., Xu, L. et al. Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol 65, 97–105 (2009). https://doi.org/10.1007/s00280-009-1008-7

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  • DOI: https://doi.org/10.1007/s00280-009-1008-7

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