Pharmacological Classification
- Antineoplastic – Multitargeted Tyrosine Kinase Inhibitor (TKI)
- Targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α/β, FGFR, KIT, RET.
- Classified as an antiangiogenic agent → blocks tumor blood vessel growth.
Mechanism of Action
- Inhibits multiple tyrosine kinases involved in angiogenesis and tumor growth.
- VEGFR inhibition → reduces endothelial cell proliferation and angiogenesis.
- PDGFR/FGFR inhibition → impairs tumor cell proliferation and survival.
- Ultimately: starves tumors of blood supply + direct antiproliferative effects.
Approved Indications
- Advanced renal cell carcinoma (RCC).
- Advanced soft tissue sarcoma (STS) (after prior chemotherapy).
(Sometimes used off-label in other solid tumors under trial settings.)
Dosing
- 800 mg orally once daily
- Take on an empty stomach (1 hr before or 2 hrs after meals).
- Swallow tablets whole; do not crush (increased absorption/toxicity).
- Dose adjustments:
- Hepatic impairment (Child-Pugh B: reduce to 200 mg daily).
- Toxicity management → stepwise reductions (800 → 600 → 400 → 200 mg).
Adverse Effects & Toxicities
Boxed Warning
- Hepatotoxicity → severe and sometimes fatal liver injury.
Key Toxicities
- Hypertension (very common; may be severe, early onset).
- Hepatotoxicity (↑ AST/ALT, bilirubin).
- QT prolongation, torsades risk.
- Cardiac dysfunction/heart failure (less common than ponatinib, but possible).
- Proteinuria, nephrotic syndrome.
- Hemorrhagic events (epistaxis, GI bleeding, CNS hemorrhage).
- GI toxicity: diarrhea, nausea, vomiting, anorexia.
- Dermatologic: hair color changes (depigmentation), rash, hand-foot syndrome.
- Thromboembolic events (arterial and venous).
- Hypothyroidism.
- Wound healing complications (hold drug before surgery).
Monitoring
- Baseline and periodic:
- LFTs (AST, ALT, bilirubin): baseline, q2 weeks × 2 months, then monthly.
- Blood pressure: baseline & frequently during first weeks, then ongoing.
- ECG & electrolytes (K, Mg, Ca): QT prolongation risk.
- Urinalysis: monitor for proteinuria.
- TSH: baseline & periodically (hypothyroidism).
- Hold/adjust if LFTs >3–8× ULN or bilirubin >2× ULN.
Drug Interactions
- CYP3A4 substrate →
- Strong inhibitors (ketoconazole, clarithromycin, ritonavir) ↑ toxicity risk.
- Strong inducers (rifampin, phenytoin, carbamazepine, St. John’s Wort) ↓ efficacy.
- pH-dependent solubility: PPIs/H2 blockers/antacids ↓ absorption.
- QT prolonging drugs → additive risk.
- Antihypertensives may be required for BP control.
- Avoid concurrent hepatotoxic agents if possible.
Pharmacist Role
- Verify appropriateness: Advanced RCC or STS, no contraindications.
- Optimize administration:
- Take on empty stomach (bioavailability ↑ 2x with food).
- Avoid crushing → altered exposure.
- Monitor & manage toxicities:
- BP control (start/adjust antihypertensives early).
- LFT surveillance; dose adjust promptly for hepatotoxicity.
- ECG monitoring in patients at risk of arrhythmia.
- Educate on bleeding risk and wound healing delays.
- Counseling:
- Signs of liver injury: jaundice, dark urine, abdominal pain.
- Report severe diarrhea, bleeding, chest pain, or SOB immediately.
- Hair color change is benign.
- Use effective contraception (teratogenic).
- Stop at least 1 week before surgery (restart after wound healing).
- Check interactions: CYP3A4, PPIs/H2 blockers, QT-prolonging meds.
Summary
Pazopanib is a multitarget TKI (VEGFR/PDGFR/FGFR inhibitor) used in advanced RCC and STS. Its efficacy comes at the cost of hepatotoxicity, hypertension, and cardiac risks, which require close pharmacist-led monitoring (LFTs, BP, ECG, urinalysis). The pharmacist’s role is pivotal in managing drug interactions, preventing toxicities, and ensuring patient adherence to empty-stomach dosing.