What is the mechanism of action, adverse effects, and contraindications of Votrient (pazopanib)?

Votrient (Pazopanib): Mechanism of Action, Adverse Effects, and Contraindications

Mechanism of Action

Pazopanib is an oral multi-tyrosine kinase inhibitor that blocks angiogenesis by targeting VEGFR-1, -2, and -3, PDGFR-α and -β, FGFR-1 and -3, c-KIT, and other kinases involved in tumor vascularization and growth. 1

• Pazopanib inhibits ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors in vitro, and blocks VEGF-induced VEGFR-2 phosphorylation in vivo, thereby suppressing tumor angiogenesis and the growth of human tumor xenografts in mice 1
• The drug also inhibits interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms) 1

Adverse Effects

Common Adverse Reactions (≥20%)

The most frequently reported adverse effects include diarrhea (52%), hypertension (40%), hair color changes (38%), nausea (26%), anorexia (22%), vomiting (21%), fatigue (19%), and weakness (14%). 2

Critical Grade 3/4 Toxicities Requiring Monitoring

• Hepatotoxicity is the most notable severe toxicity, with elevated alanine transaminase (30%) and aspartate transaminase (21%) at grade 3 levels, mandating liver function monitoring before and during treatment 2
• Hypertension occurs in 40% of patients (any grade), with 4% experiencing grade 3 events 1
• Cardiac rhythm irregularities have been associated with pazopanib use 2

Laboratory Abnormalities

• ALT elevation (53% any grade, 10% grade 3,2% grade 4) 1
• AST elevation (53% any grade, 7% grade 3, <1% grade 4) 1
• Leukopenia (37% any grade), neutropenia (34% any grade), thrombocytopenia (32% any grade), and lymphocytopenia (31% any grade, 4% grade 3) 1

Serious Adverse Events

• Hemorrhagic events, including pulmonary and gastrointestinal hemorrhage 1
• Arterial and venous thromboembolic events 1
• Gastrointestinal perforation and fistula formation 1
• Thrombotic microangiopathy (TMA) 1
• Interstitial lung disease (ILD)/pneumonitis 1
• Posterior reversible encephalopathy syndrome (PRES) 1
• Proteinuria 1
• Hypothyroidism 1
• Tumor lysis syndrome 1
• QT prolongation and torsades de pointes 1

Contraindications and Critical Warnings

Absolute Contraindications

• Pazopanib is contraindicated in combination with other cancer therapies, as clinical trials combining pazopanib with pemetrexed and lapatinib were terminated early due to increased toxicity and mortality, including fatal pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death 1

Hepatic Impairment

• Pazopanib is not recommended in patients with moderate (total bilirubin >1.5 to 3 × ULN and any ALT) or severe (total bilirubin >3 × ULN and any ALT) hepatic impairment 1
• No dose adjustment is required for mild hepatic impairment (total bilirubin ≤ULN and ALT >ULN, or bilirubin >1 to 1.5 × ULN and any ALT) 1
• The maximum tolerated dose in moderate hepatic impairment is 200 mg once daily 1

Pregnancy and Reproductive Considerations

• Pazopanib can cause fetal harm based on animal studies showing maternal toxicity, teratogenicity, and abortion at exposures lower than the maximum recommended human dose 1
• Females of reproductive potential must use effective contraception during treatment and for at least 2 weeks after the final dose 1
• Males (including those with vasectomies) with female partners of reproductive potential must use condoms during treatment and for at least 2 weeks after the last dose 1

Pediatric Population

• Pazopanib is not indicated for pediatric use and may have severe effects on organ growth and maturation in patients younger than 2 years based on its mechanism of action 1

Drug Interactions

• Pazopanib is primarily metabolized by CYP3A4, requiring caution with concomitant CYP3A4 inducers or inhibitors 1
• Pazopanib is a substrate for P-gp and BCRP 1

Administration Considerations

• Pazopanib must be administered on an empty stomach (at least 1 hour before or 2 hours after a meal) as food increases AUC and Cmax approximately 2-fold 1
• Tablets must not be crushed, as crushing increases AUC by 46% and Cmax by approximately 2-fold 1

Geriatric Considerations

• Patients ≥65 years have higher incidences of grade 3/4 fatigue (19% vs 12%), hypertension (10% vs 6%), decreased appetite (11% vs 2%), and ALT/AST elevations compared to younger patients 1