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Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain1. Concerns over hepatotoxicity have contributed to the withdrawal or non-approval of lumiracoxib in most major drug markets worldwide. We performed a case-control genome-wide association study on 41 lumiracoxib-treated patients with liver injury (cases) and 176 matched lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 × 10^sup -10^). These findings were replicated in an independent set of 98 lumiracoxib-treated cases and 405 matched lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 × 10^sup -12^). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501-HLA-DQB1*0602-HLA-DRB5*0101-HLA-DQA1*0102, most significant allele P = 6.8 × 10^sup -25^, allelic odds ratio = 5.0, 95% CI 3.6-7.0). These results offer the potential to improve the safety profile of lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from lumiracoxib treatment.
Idiosyncratic drug-induced liver injury (DILI) is a major safety concern and has been a common cause for the marketing withdrawal of a wide range of drugs2.4. Most drugs causing severe idiosyncratic liver injury show no signs of hepatotoxicity in preclinical animal models and have very low rates of hepatotoxicity in humans; these drugs have an estimated incidence of liver transplantation or death in humans of .1 per 10,000 individuals taking the drug5. Due to the unpredictable and rare nature of these events, it is often not until the post-marketing stage, during which a large number of patients are exposed to the drug, that a drug's propensity for idiosyncratic liver injury is revealed; these events usually result in the marketing withdrawal of the drug. The discovery of genetic markers able to identify individuals at risk for developing DILI could potentially make otherwise safe and efficacious drugs available for use.
Lumiracoxib (Prexige/Joicela), a selective cyclooxygenase-2 (COX-2) inhibitor, has been shown to be efficacious in the symptomatic treatment of osteoarthritis and acute pain1. The risk of developing cardiovascular events, a major safety concern with selective COX-2 inhibitors, has been shown for lumiracoxib to be similar to nonsteroidal anti-inflammatory drugs6,7. However, concern over hepatotoxicity has led to market withdrawal or nonapproval of lumiracoxib...