title: Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors.
abstract: Tyrosine kinase inhibitors (TKIs) represent important therapeutic alternatives to, or combinations with, traditional cytotoxic chemotherapy. Despite their selective molecular targeting and demonstrated clinical benefit, TKIs produce a range of serious adverse events, including drug-induced liver injury, that require careful patient management to maintain treatment benefit without harm. Genetic characterization of serious adverse events can identify mechanisms of injury and improve safety risk management. This review presents pharmacogenetic comparisons of two approved TKIs, lapatinib and pazopanib, which reveal different mechanisms of injury and inform the characteristics and risk of serious liver injury in treated patients. The data presented demonstrate the utility of genetic studies to investigate drug-induced liver injury and potentially support its management in patients.
authors.affiliation: Genetics, Quantitative Sciences, GlaxoSmithKline Research & Development, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. colin.f.spraggs@gsk.com
authors.forename: Colin F
authors.initials: CF
authors.lastname: Spraggs
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hunt
mesh_terms: D054316:Biomarkers, Pharmacological; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000235:genetics*; D005878:Gilbert Disease / Q000188:drug therapy / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007191:Indazoles; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D011743:Pyrimidines / Q000008:administration & dosage / Q000633:toxicity; D011799:Quinazolines / Q000008:administration & dosage / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity; D000099148:UGT1A1 Enzyme
chemical_list: D054316:Biomarkers, Pharmacological; D014453:Glucuronosyltransferase; D007191:Indazoles; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C516667:pazopanib