Gene:

UGT1A1

UDP glucuronosyltransferase 1 family, polypeptide A1

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for irinotecan based on UGT1A1 genotype (PMID:21412232). They recommend reducing the dose for *28 homozygous patients receiving more than 250 mg/m^2.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.

The FDA recommends, but does not require, genetic testing prior to initiating treatment with irinotecan.

Excerpt from the irinotecan drug label:

Individuals who are homozygous for the UGT1a1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of CAMPTOSAR treatment...When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele.

Patients homozygous for the UGT1A1*28 allele, a genetic polymorphism present in approximately 10% of the North American population that leads to reduced UGT1A1 enzyme activity, are at increased risk for neutropenia resulting from treatment with irinotecan. Individuals heterozygous for the UGT1A1 allele may be at increased risk for neutropenia. UGT1A1 catalyzes the conjugation of the highly active irinotecan metabolite SN-38 to the less-active SN-38 glucuronide.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the irinotecan drug label, updated on 5/2010 to include more studies supporting the association of UGT1A1*28 and neutropenia risk and information about laboratory testing of UGT1A1.

Nilotinib is indicated by the FDA for use in patients diagnosed with Philadelphia chromosome positive chronic myeloid leukemia.

Excerpts from the nilotinib drug label:

"Treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The study is ongoing and further data will be required to determine long-term outcome. (1.1) Treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. (1.2)"

"Mechanism of Action Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML."

SUMMARY
Nilotinib is indicated for the treatment of chronic myeloid leukemia diagnosed as Philadelphia chromosome positive. The drug label includes recommended dosing guidelines for newly diagnosed individuals and for those resistant or intolerant to previous treatments.

The FDA recommends, but does not require, genetic testing for UGT1A1 variants prior to initiating or reinitiating treatment with nilotinib.

Excerpt from the nilotinib drug label:

"Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients (see Warnings and Precautions (5.5))."

SUMMARY
Nilotinib is an inhibitor of UGT1A1 in vitro, and individuals with the UGT1A1*28 genotype (TA)7/(TA)7 (rs8175347) are at an increased risk of hyperbilirubinemia when taking nilotinib. The drug can also inhibit ABCB1, and can inhibit or induce numerous CYP enzymes, thus may affect the pharmacokinetics of drugs taken concomitantly (as discussed in section 7.1). The label also indictates that CYP3A4 inhibitors or inducers should be avoided when taking nilotinib due to the possible effect on nilotinib pharmacokinetics and efficacy.

For the complete drug label text with sections containing this pharmacogenetic information highlighted, see the Nilotinib drug label.

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