The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer.
OBJECTIVE
UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.


METHODS
In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.


RESULTS
UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant.


CONCLUSIONS
The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.
Toffoli
Giuseppe
G
Experimental and Clinical Pharmacology Unit, Medical Oncology unit of Centro di Riferimento Oncologico, National Cancer Institute, via Pedemontana Occidentale, 12, 33081, Aviano, Italy. gtoffoli@cro.it
Cecchin
Erika
E
Corona
Giuseppe
G
Russo
Antonio
A
Buonadonna
Angela
A
D'Andrea
Mario
M
Pasetto
Lara Maria
LM
Pessa
Sergio
S
Errante
Domenico
D
De Pangher
Vincenzo
V
Giusto
Mauro
M
Medici
Michele
M
Gaion
Fernando
F
Sandri
Paolo
P
Galligioni
Enzo
E
Bonura
Salvatore
S
Boccalon
Massimo
M
Biason
Paola
P
Frustaci
Sergio
S
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016896:Treatment Outcome
D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin