The treatment phase is continuing treatment beyond 3 months.
The patient has been issued an authority prescription for pazopanib.
The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours.
This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.
Pazopanib has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer, though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.
Contraindications
The only contraindication is hypersensitivity to pazopanib or any of its excipients. Cautions include:
Hypertension, including hypertensive crises have been reported.
It has one black box warning by the US FDA, namely severe hepatotoxicity including fatalities.
Adverse effects
The most common side effects of pazopanib are nausea, vomiting, diarrhoea, changes in hair colour, hypertension, appetite loss, hyperglycaemia, hypoglycaemia, electrolyte abnormalities, laboratory anomalies, oedema, hair loss or discolouration, taste changes, abdominal pain, rash, fatigue and bone marrow suppression. It has been associated with a low, but real risk of potentially fatal liver damage.
Overdose
The treatment for overdose is purely supportive and the symptoms include grade 3 hypertension and fatigue.
Interactions
Drug interactions include:
Co-administration with strong inhibitors of the liver enzyme CYP3A4 may increase pazopanib serum levels as it is a CYP3A4 substrate.
CYP3A4 inducers decrease pazopanib serum levels.
It is a p-glycoprotein substrate and hence PGP inhibitors such as quinidine may interact with pazopanib.
Pazopanib is not a substrate for either of the liver enzymes OATP1B1 and OATP1B3.
Pazopanib has inhibitory potency towards OATP1B1 but not for OATP1B3.
After oral intake of a single tablet, pazopanib has a bioavailability of 21% with a range of 14–39% between people. It reaches highest concentrations in the blood plasma after median 3.5 hours; the range in studies was 1.0 to 11.9 hours. When taken regularly, the area under the curve increases 1.23- to 4-fold as compared to a single dose. Taking the drug together with food approximately doubles the AUC as well as the highest plasma concentrations ; and crushing the tablet increases the AUC 1.46-fold, as well doubling the Cmax. When in the bloodstream, more than 99.5% of the substance are bound to plasma proteins. The liver enzyme mainly responsible for metabolizing the drug is CYP3A4; and there are minor contributions from CYP1A2 and CYP2C8. Metabolites identified in tests with human liver cells and microsomes include various hydroxyl derivatives and possibly a carboxylic acid. Only 6% of the circulating substance is in the form of metabolites, and all but one of them are 10- to 20-fold less active than pazopanib itself. Consequently, the metabolites are not considered important for the drug's therapeutic effect. Pazopanib is eliminated with a biological half-life of 30.9±4 hours on average mainly via the faeces. Less than 4% are eliminated via the urine.
