Pazopanib

Pazopanib (brand name Votrient) is an oral medication classified as a tyrosine kinase inhibitor. It is approved for the treatment of certain types of cancer, including advanced renal cell carcinoma and soft tissue sarcoma.

Pazopanib works by blocking multiple receptors, such as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and c-Kit, which play key roles in tumor blood vessel formation and growth.

By inhibiting these pathways, pazopanib reduces tumor vascularization and proliferation, ultimately slowing cancer progression.

UGT1A1 is the primary gene of interest for pazopanib pharmacogenomics. UGT1A1 encodes an enzyme in the liver responsible for glucuronidation, a process that attaches glucuronic acid to bilirubin and certain drugs to facilitate their elimination from the body.

Variations in UGT1A1 can alter enzyme activity. Reduced-function variants (often called poor metabolizers) can lead to higher levels of bilirubin and increased risk of jaundice or hyperbilirubinemia when pazopanib inhibits UGT1A1 activity.

Patients classified as UGT1A1 poor metabolizers have reduced enzyme activity and, when treated with pazopanib—which itself can inhibit UGT1A1—are at higher risk for elevated bilirubin levels and related liver toxicity. Normal and intermediate metabolizers generally process bilirubin and the drug without significant changes, while indeterminate or unavailable genotypes should follow standard dosing with monitoring.

Normal Metabolizer

• Effect on drug levels: Standard bilirubin conjugation and elimination, typical pazopanib clearance.
• Clinical consequence: Standard safety profile; no dose adjustment needed.
• Side effects: Expected side effects include hypertension, diarrhea, nausea; severity and frequency as in general population.

Intermediate Metabolizer

• Effect on drug levels: Slightly reduced UGT1A1 activity may lead to mild bilirubin increase.
• Clinical consequence: Generally well-tolerated; monitoring of liver function advised.
• Side effects: Occasional mild hyperbilirubinemia; severity typically mild and transient.

Poor Metabolizer

• Effect on drug levels: Significantly reduced UGT1A1 activity, higher bilirubin accumulation.
• Clinical consequence: Increased risk of jaundice and liver toxicity (hyperbilirubinemia).
• Side effects: Moderate to severe hyperbilirubinemia; may require treatment interruption or dose reduction.

Indeterminate

• Effect on drug levels: Unknown impact on UGT1A1 activity.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Monitor liver enzymes and bilirubin as per routine care.

Not Available

• Effect on drug levels: Unknown impact on UGT1A1 activity.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Monitor liver enzymes and bilirubin as per routine care.

UGT1A1 Dosing Guideline

No alternative agents or dosing adjustments are specified in FDA pharmacogenetic guidance for pazopanib. Consult oncology guidelines for other therapeutic options if UGT1A1 status is a concern.

• FDA – Table of Pharmacogenetic Associations