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Denlinger CS , Blanchard R , Xu L , Bernaards C , Litwin S , Spittle C , Berg DJ , McLaughlin S , Redlinger M , Dorr A , Hambleton J , Holden S , Kearns A , Kenkare-Mitra S , Lum B , Meropol NJ , O'Dwyer PJ
Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors
Cancer Chemotherapy and Pharmacology. 2009 Dec;65(1) :97-105
PMID: 19415281 PMCID: PMC2746259 URL: https://www.ncbi.nlm.nih.gov/pubmed/19415281
AbstractThe 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. 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. Forty-five subjects were enrolled. No difference in dose-normalized AUC(0-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. Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.
NotesDenlinger, Crystal S. Blanchard, Rebecca Xu, Lu Bernaards, Coen Litwin, Samuel Spittle, Cynthia Berg, Daniel J. McLaughlin, Susan Redlinger, Maryann Dorr, Andrew Hambleton, Julie Holden, Scott Kearns, Anne Kenkare-Mitra, Sara Lum, Bert Meropol, Neal J. O'Dwyer, Peter J. Springer New york 495tb