Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics.
OBJECTIVE
We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients.


METHODS
Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated.


RESULTS
Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes.


CONCLUSIONS
On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.
Innocenti
Federico
F
The University of Chicago, Chicago, IL 60637, USA. finnocen@medicine.bsd.uchicago.edu
Kroetz
Deanna L
DL
Schuetz
Erin
E
Dolan
M Eileen
ME
Ramírez
Jacqueline
J
Relling
Mary
M
Chen
Peixian
P
Das
Soma
S
Rosner
Gary L
GL
Ratain
Mark J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001663:Bilirubin / Q000097:blood; D001711:Biotransformation / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D020022:Genetic Predisposition to Disease; D020719:Glucuronides / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D018579:Patient Selection; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D051538:Hepatocyte Nuclear Factor 1-alpha; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D000099148:UGT1A1 Enzyme; C441475:7-ethyl-10-hydroxycamptothecin glucuronide; C000715087:ABCC2 protein, human; C496487:HNF1A protein, human; C503999:SLCO1B1 protein, human; C421109:multidrug resistance-associated protein 1