Introduction
Votrient (pazopanib hydrochloride) is an oral multitargeted tyrosine kinase inhibitor developed by GlaxoSmithKline and approved by the FDA in 2009. It represents an important therapeutic option in the management of advanced renal cell carcinoma and soft tissue sarcoma. This targeted therapy inhibits multiple pathways involved in tumor growth and angiogenesis, offering a distinct mechanism of action compared to traditional chemotherapy.
Mechanism of Action
Pazopanib is a potent multi-targeted tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors (VEGFR-1, -2, and -3), platelet-derived growth factor receptors (PDGFR-α and -β), fibroblast growth factor receptor (FGFR-1 and -3), cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). By blocking these receptors, pazopanib inhibits angiogenesis and tumor cell proliferation, ultimately leading to reduced tumor growth and potential tumor regression.
Indications
- Advanced renal cell carcinoma (RCC)
- Advanced soft tissue sarcoma (STS) in patients who have received prior chemotherapy
Dosage and Administration
Standard dosing: 800 mg orally once daily Administration: Should be taken without food (at least 1 hour before or 2 hours after a meal) Dose modifications:- Hepatic impairment: Reduce dose to 200 mg daily in patients with moderate hepatic impairment
- Strong CYP3A4 inhibitors: Consider reducing dose to 400 mg daily
- Strong CYP3A4 inducers: Avoid concomitant use or consider dose increase
- Renal impairment: No dose adjustment necessary
Pharmacokinetics
Absorption: Peak plasma concentrations achieved within 2-4 hours; bioavailability approximately 14-39% Distribution: Extensive tissue binding; >99% protein bound Metabolism: Primarily hepatic via CYP3A4 with minor contributions from CYP1A2 and CYP2C8 Elimination: Primarily fecal excretion (≈82%) with renal elimination accounting for <4% Half-life: Approximately 30.9 hoursContraindications
- Hypersensitivity to pazopanib or any component of the formulation
- Severe hepatic impairment
Warnings and Precautions
Boxed Warning: Hepatotoxicity - Severe and fatal hepatotoxicity has occurred. Monitor hepatic function before and during treatment. Additional warnings:- QT prolongation and torsades de pointes
- Hemorrhagic events
- Arterial thromboembolic events
- Gastrointestinal perforation and fistula
- Hypertension
- Thyroid dysfunction
- Proteinuria
- Reversible posterior leukoencephalopathy syndrome (RPLS)
- Wound healing complications
Drug Interactions
Strong CYP3A4 inhibitors: Avoid concomitant use (e.g., ketoconazole, ritonavir, clarithromycin) Strong CYP3A4 inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) Drugs that prolong QT interval: Use with caution (e.g., antiarrhythmics, certain antipsychotics) P-gp substrates: May increase concentrations of drugs that are P-gp substratesAdverse Effects
Common adverse reactions (≥20%):- Diarrhea (52%)
- Hypertension (40%)
- Hair color changes (38%)
- Nausea (26%)
- Anorexia (22%)
- Vomiting (21%)
- Fatigue (19%)
- Asthenia (14%)
- Abdominal pain (11%)
- Hepatotoxicity (18% Grade 3-4)
- Hemorrhagic events (13%)
- Arterial thromboembolic events (3%)
- Gastrointestinal perforation (1%)
- QT prolongation
Monitoring Parameters
Baseline and periodic monitoring:- Liver function tests (ALT, AST, bilirubin) - weekly for first 9 weeks, then every 4 weeks
- Blood pressure - weekly for first 6 weeks, then regularly
- ECG for QT prolongation
- Thyroid function tests
- Urinalysis for proteinuria
- Complete blood count
- Electrolytes (especially magnesium, potassium, calcium)
Patient Education
- Take on an empty stomach (1 hour before or 2 hours after meals)
- Do not crush or break tablets
- Report any signs of liver problems (yellowing skin/eyes, dark urine, abdominal pain)
- Monitor blood pressure regularly as directed
- Report unusual bleeding or bruising
- Inform all healthcare providers about Votrient use before any surgical procedures
- Use effective contraception during treatment and for at least 2 weeks after discontinuation
- Be aware of potential hair color changes (usually reversible)
- Report severe diarrhea, nausea, or vomiting
- Avoid grapefruit and grapefruit juice during treatment
References
1. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068. 2. van der Graaf WT, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. 3. Votrient® (pazopanib) prescribing information. Novartis Pharmaceuticals Corporation. 4. Hutson TE, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010;28(3):475-480. 5. National Comprehensive Cancer Network (NCCN) Guidelines. Kidney Cancer Version 4.2023. 6. FDA Drug Safety Communication: Boxed warning added to pazopanib for risk of severe hepatotoxicity. October 2010.