Pazopanibum
Pazopanibum Uses, Dosage, Side Effects, Food Interaction and all others data.
Pazopanibum is a multi-tyrosine kinase inhibitor of vascular endothelial growth factorreceptor (VEGFR)- 1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokinereceptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.
Pazopanibum 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.
Trade Name | Pazopanibum |
Availability | Prescription only |
Generic | Pazopanib |
Pazopanib Other Names | Pazopanib, Pazopanibum |
Related Drugs | Keytruda, pembrolizumab, doxorubicin, Avastin, bevacizumab, Opdivo, Adriamycin, Afinitor, Votrient, Yondelis |
Type | |
Formula | C21H23N7O2S |
Weight | Average: 437.518 Monoisotopic: 437.163393705 |
Protein binding | >99% protein bound, independent of concentrations over a range of 10-100 μg/mL. |
Groups | Approved |
Therapeutic Class | Targeted Cancer Therapy |
Manufacturer | |
Available Country | |
Last Updated: | September 19, 2023 at 7:00 am |
Uses
Pazopanibum is used for the treatment of patients with advanced renal cell carcinoma (RCC). Pazopanibum is used for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
Pazopanibum is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Advanced Soft Tissue Sarcoma, Advanced Thyroid cancer
How Pazopanibum works
Pazopanibum 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.
Dosage
Pazopanibum dosage
Recommended Dosing: The recommended starting dose of Pazopanibum is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). The dose of Pazopanibum should not exceed 800 mg.
Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.
Dose Modification Guidelines:
- In advancedrenal cell carcinoma, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability.
- In advancedsoft tissue sarcoma, a decrease or increase should be in 200-mg steps based on individual tolerability.
Hepatic Impairment
: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to Pazopanibum should be considered. If Pazopanibum is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. Pazopanibum is not recommended in patients with severe hepatic impairment
Side Effects
Common side effects of Pazopanibum include:
- headache
- loss of appetite
- weight loss
- altered sense of taste
- nausea and vomiting (may be severe)
- diarrhea
- numbness/tingling/redness in hands/feet
- changes in hair or skin color
- joint or muscle pain, or
- feeling tired/weak.
Precaution
Hepatic Toxicity and Hepatic Impairment, QT Prolongation, Cardiac Dysfunction, Hemorrhagic Events, Thromboembolic Events, Gastrointestinal Perforation and Fistula, Hypertension, Hypothyroidism, Pregnancy.
Interaction
Co-administration with CYP3A4 (eg, itraconazole, clarithromycin, atazanavir, idinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), P-gp & BCRP inhibitors, high-/low-fat food increases exposure & cone of pazopanib. Co-administration with CYP3A4 (eg, rifampicin) inducers may decrease plasma pazopanib cone. P-gp & BCRP inducers may alter exposure & distribution of pazopanib.
Pazopanibum may alter exposure & distribution of CYP3A4 substrates (eg, midazolam), CYP2C8 substrates (eg, paclitaxel) & UGT1A1 substrates (eg, irinotecan & its active metabolite SN-38). Pazopanibum may increase the ratio of dextrometrophan to dextrophan cone after administration of dextrometrophan. Proton-pump inhibitors (eg, esomeprazole) & other agents that increase gastric pH may decrease bioavailability of pazopanib. Concomitant use with simvastatin & other statins may lead to ALT elevations.
Food Interaction
- Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of pazopanib.
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of pazopanib.
- Take on an empty stomach. Separate pazopanib from meals by at least 1 hour before and 2 hours after eating as food increases pazopanib bioavailability.
- Take separate from antacids. Separate the administration of pazopanib and antacids by several hours.
[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pazopanib.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.
Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.
ADJUST DOSING INTERVAL: Food increases the oral bioavailability of pazopanib.
The mechanism of interaction is unknown.
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in peak plasma concentration (Cmax) and systemic exposure (AUC).
MANAGEMENT: Patients treated with pazopanib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.
Pazopanibum should be administered at least one hour before or two hours after a meal.
Pazopanibum Drug Interaction
Major: diltiazem, omeprazoleModerate: everolimus, albuterol / ipratropium, prochlorperazine, rosuvastatin, atorvastatin, sorafenib, sunitinibUnknown: contained in alcoholic beverages , ubiquinone, alendronate, levetiracetam, metoprolol, morphine, acetaminophen, metoclopramide, vitamin a topical, montelukast, cholecalciferol
Pazopanibum Disease Interaction
Major: bleeding, liver dysfunction, GI perforationModerate: CV disease, hypothyroidism, lung dysfunction, QT prolongation, hypertension, PRES, proteinuria, thromboembolic disorders
Volume of Distribution
Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4)
Elimination Route
Absorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;
Half Life
35 hours. Oral absorption is not the rate limiting step of elimination from the plasma.
Clearance
CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism.
Elimination Route
Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.
Pregnancy & Breastfeeding use
Pazopanibum can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Pazopanibum is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient.
There are no adequate and well-controlled studies of Pazopanibum in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Pazopanibum
Contraindication
Hypersensitivity.
Acute Overdose
Pazopanibum doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.
Treatment of overdose with Pazopanibum should consist of general supportive measures. There is no specific antidote for overdosage of Pazopanibum.
Hemodialysis is not expected to enhance the elimination of Pazopanibum because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.
Innovators Monograph
You find simplified version here Pazopanibum
Pazopanibum contains Pazopanib see full prescribing information from innovator Pazopanibum Monograph, Pazopanibum MSDS, Pazopanibum FDA label