title: Influence of UGT1A1 6, 27, and 28 polymorphisms on nilotinib-induced hyperbilirubinemia in Japanese patients with chronic myeloid leukemia.
abstract: Nilotinib potently inhibits human uridine diphosphate-glucuronosyltransferase (UGT1A1) activity, causing hyperbilirubinemia. We investigated the influence of UGT1A1 polymorphisms and nilotinib plasma trough concentrations (C0) on nilotinib-induced hyperbilirubinemia in 34 Japanese patients with chronic myeloid leukemia (CML). The proportion of patients with hyperbilirubinemia was significantly higher among patients with the UGT1A1*6/*6 and *6/*28 genotypes (poor metabolizers) than among those with other genotypes (p = 0.004). The median time to elevation of bilirubin levels in UGT1A1 poor metabolizers was 2.0 weeks (hazard ratio, 6.11). The median time to reduction in nilotinib dose in UGT1A1 poor metabolizers was 4.0 weeks (hazard ratio, 7.52; p = 0.002). Consequently, in the maintenance phase 3 months following the initiation of nilotinib therapy, the median daily dose and C0 of nilotinib were 350 mg/day and 372 ng/mL, respectively, in UGT1A1 poor metabolizers, and 600 mg/day and 804 ng/mL, respectively, in the other patients. Patients at increased hyperbilirubinemia risk could be identified by prospective UGT1A1 genotyping prior to nilotinib therapy. To avoid an interruption of CML treatment due to nilotinib-induced hyperbilirubinemia, it may be beneficial to reduce the initial nilotinib dose to 300-400 mg/day for UGT1A1 poor metabolizers.
authors.affiliation: Department of Pharmacy, Akita University Hospital.
authors.forename: Maiko
authors.initials: M
authors.lastname: Abumiya
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kameoka
authors.forename: Naohito
authors.initials: N
authors.lastname: Fujishima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sawada
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D044466:Asian People / Q000235:genetics*; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D054796:Drug Dosage Calculations; D005260:Female; D020022:Genetic Predisposition to Disease; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology* / Q000208:ethnology; D007564:Japan / Q000453:epidemiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D001663:Bilirubin; D015415:Biomarkers; D014453:Glucuronosyltransferase; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000099148:UGT1A1 Enzyme; C498826:nilotinib