AI Article Synopsis
- Nilotinib is a more effective BCR-ABL inhibitor than imatinib, showing improved potency and selectivity in treating certain leukemias.
- Instances of temporarily increased bilirubin levels were noted during clinical studies, linked to a genetic variation in the UGT1A1 gene that processes bilirubin.
- The combination of nilotinib's inhibition of UGT1A1 and the genetic polymorphism likely contributes to the higher incidence of hyperbilirubinemia observed in patients.
Article Abstract
Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.
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| http://dx.doi.org/10.1038/sj.leu.2404827 | DOI Listing |
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