Nilotinib

Nilotinib (brand name Tasigna) is an oral tyrosine kinase inhibitor specifically designed to target the BCR-ABL protein produced by the Philadelphia chromosome abnormality in certain leukemia cells.

It is primarily used to treat chronic myeloid leukemia (CML) in patients who are newly diagnosed in the chronic phase or those who have shown resistance or intolerance to prior therapies. By blocking BCR-ABL kinase activity, nilotinib helps to slow the uncontrolled growth of leukemic cells.

The drug works by binding to the ATP-binding pocket of the BCR-ABL enzyme, preventing phosphorylation and downstream signaling. This selective inhibition reduces proliferation of malignant cells and helps to achieve and maintain remission in CML patients.

UGT1A1 is a liver enzyme responsible for adding glucuronic acid to bilirubin and certain drugs, a process called glucuronidation. This modification makes compounds more water-soluble and easier to excrete.

Variations in the UGT1A1 gene can alter how efficiently this enzyme functions. Reduced activity variants may slow elimination of bilirubin and nilotinib metabolites, leading to higher circulating levels and risk of side effects such as hyperbilirubinemia.

Genetic differences in UGT1A1 activity classify patients into metabolizer phenotypes, from ultra-rapid to poor metabolizers. Poor metabolizers often experience higher bilirubin levels and may be at increased risk of toxicity, while ultra-rapid metabolizers may clear the drug more quickly, potentially reducing efficacy.

Ultra-rapid/Rapid Metabolizer

• Effect on drug levels: Lower than expected nilotinib exposure due to faster clearance.
• Clinical consequence: Potential for reduced therapeutic efficacy.
• Side effects: Generally fewer bilirubin-related effects; mild headache or GI symptoms.

Normal Metabolizer

• Effect on drug levels: Expected nilotinib exposure and clearance.
• Clinical consequence: Standard efficacy and safety profile.
• Side effects: Typical incidence of rash, nausea, and mild QT prolongation.

Intermediate Metabolizer

• Effect on drug levels: Moderately increased nilotinib exposure and slower clearance.
• Clinical consequence: Slightly higher risk of elevated bilirubin.
• Side effects: Occasional mild to moderate hyperbilirubinemia; monitoring recommended.

Poor Metabolizer

• Effect on drug levels: Significantly increased nilotinib exposure and markedly slower clearance.
• Clinical consequence: Higher risk of hyperbilirubinemia and related toxicity.
• Side effects: Moderate to severe jaundice and elevated bilirubin levels; frequency varies.

Indeterminate/Not Available

• Effect: Unknown impact on nilotinib levels
• Clinical consequence: No specific guidance; follow standard dosing
• Side effects: As per general population; monitor liver function

UGT1A1 Dosing Guideline

No alternative pharmacogenetic-guided treatments or alternative dosing options are specified in the FDA guidelines for nilotinib. Clinicians may consider other tyrosine kinase inhibitors based on patient tolerance and overall treatment plan.

• FDA – Table of Pharmacogenetic Associations