Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism.
BACKGROUND
Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction.


METHODS
Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study.


RESULTS
No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes.


CONCLUSIONS
The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.
Xu
C-F
CF
GlaxoSmithKline, Research and Development, Genetics Division, New Frontiers Science Park (North), Room H30-2-060, Third Avenue, Harlow, Essex CM19 5AW, UK. chun-fang.2.xu@gsk.com
Reck
B H
BH
Xue
Z
Z
Huang
L
L
Baker
K L
KL
Chen
M
M
Chen
E P
EP
Ellens
H E
HE
Mooser
V E
VE
Cardon
L R
LR
Spraggs
C F
CF
Pandite
L
L
D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001663:Bilirubin / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000601:surgery; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D005838:Genotype; D005878:Gilbert Disease / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000453:epidemiology / Q000209:etiology; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000601:surgery; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D000099148:UGT1A1 Enzyme
D000410:Alanine Transaminase; D000970:Antineoplastic Agents; D001663:Bilirubin; D014453:Glucuronosyltransferase; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C516667:pazopanib
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