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


CONCLUSIONS
Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Crystal S
CS
Denlinger
Rebecca
R
Blanchard
Lu
L
Xu
Coen
C
Bernaards
Samuel
S
Litwin
Cynthia
C
Spittle
Daniel J
DJ
Berg
Susan
S
McLaughlin
Maryann
M
Redlinger
Andrew
A
Dorr
Julie
J
Hambleton
Scott
S
Holden
Anne
A
Kearns
Sara
S
Kenkare-Mitra
Bert
B
Lum
Neal J
NJ
Meropol
Peter J
PJ
O'Dwyer
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011355:Prodrugs; D000099148:UGT1A1 Enzyme
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D011355:Prodrugs; D000099148:UGT1A1 Enzyme