PAZITORZ 400 mg

Indications

• First-line treatment of advanced renal cell carcinoma
• Treatment of advanced renal cell carcinoma in patients who have had previous treatment with cytokine therapy
• Treatment of selective subtypes of advanced soft-tissue sarcoma

Dosage

Children: Refer to the BNF for Children for appropriate dosing information in pediatric patients.

Adults: Initial dose is 800 mg once daily, which may be adjusted in increments of 200 mg based on tolerability, with a maximum of 800 mg per day.

Mechanism of action

Pazopanib inhibits multiple tyrosine kinases, which play a significant role in the angiogenesis pathway. By blocking VEGFR and PDGFR, pazopanib interferes with the signaling required for tumor blood vessel formation, thereby inhibiting tumor growth and promoting apoptosis in cancer cells.

Pharmacodynamics

Pazopanib is a synthetic indazolylpyrimidine that achieves steady-state plasma concentrations exceeding 15 μg/ml, sufficient for maximal inhibition of VEGFR2 phosphorylation and associated anti-tumor activity. At therapeutic concentrations (0.01 - 0.084 μmol/L), it leads to a reduction in tumor blood flow, increased apoptosis, inhibition of tumor growth, and decreased interstitial fluid pressure and hypoxia within tumors.

Pharmacokinetics

Pazopanib is administered orally and is extensively metabolized in the liver, primarily by CYP3A4. Its pharmacokinetics can be influenced by hepatic and renal impairment, as well as by concurrent administration of strong CYP3A4 inhibitors or inducers, necessitating dose adjustments in such scenarios. The drug has a long half-life, allowing for once-daily dosing.

Adverse effects

• Hypertension
• Gastrointestinal fistulas
• Gastrointestinal perforation
• Hemorrhage
• Thrombotic microangiopathy
• Ischemic stroke
• Myocardial infarction
• QT-interval prolongation
• Transient ischemic attack

Interactions

• Grapefruit juice (severe - increases exposure)
• Lapatinib (severe - increases exposure)
• Dronedarone (unknown - increases exposure)
• Antifungals (azoles) (unknown - increases exposure)
• Cobicistat (unknown - increases exposure)
• Crizotinib (unknown - increases exposure)
• Dabrafenib (unknown - decreases exposure)
• Bosentan (unknown - decreases exposure)
• Idelalisib (unknown - increases exposure)
• Imatinib (unknown - increases exposure)

Precautions

• Caution in patients with hepatic impairment
• Caution in patients with renal impairment
• Monitor full blood count prior to starting therapy and at specified intervals
• Patients should be monitored for signs of hypertension and treated as required
• Consider the risk of aneurysm and artery dissection in patients with risk factors

Pregnancy

Manufacturer advises to avoid due to potential toxicity observed in animal studies.

Breast-feeding

Manufacturer advises to avoid as no information is available.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Tablets

Mechanism of action

Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth. Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. /SRP: triple negative = breast cancers lacking all three common targets of chemotherapy: the estrogen receptor, the progesterone receptor and Her2/neu, the epidermal growth factor receptor 2/ Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor beta (at tyrosine 751; p751-PDGFRbeta) was identified around perivascular brain micrometastases. p751-PDGFRbeta(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, /it was/ reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. /In this study/ the effect of pazopanib on the brain neuroinflammatory microenvironment /was evaluated/. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRbeta(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.

Pharmacodynamics

Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.