Subject(s)
Alanine Transaminase/blood , Anticholesteremic Agents/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms/blood , Pyrimidines/pharmacology , Simvastatin/pharmacology , Sulfonamides/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/genetics , Clinical Trials as Topic , Drug Interactions , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Incidence , Indazoles , Neoplasm Proteins/genetics , Neoplasms/drug therapy , Polymorphism, Single Nucleotide , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Reference Values , Simvastatin/adverse effects , Simvastatin/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic useABSTRACT
Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.
Subject(s)
Amino Acid Substitution/genetics , Coronary Disease/genetics , Mutation , Phospholipases A2/genetics , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Alleles , Coronary Disease/drug therapy , Enzyme Inhibitors/therapeutic use , Genetics, Population , Homozygote , Humans , Phospholipase A2 Inhibitors , Phospholipases A2/metabolism , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , White People/geneticsABSTRACT
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.