Mechanism of Action
Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-alpha and -beta, 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). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit and PDGFR-beta 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.
Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.
The QT prolongation potential of pazopanib was assessed as part of an uncontrolled. open-label, dose escalation study in advanced cancer patients. Sixty-three patients received doses of pazopanib ranging from 50 to 2,000 mg daily. Serial ECGs were collected on Day 1 and single pre-dose ECGs were collected on Days 8, 15, and 22 to evaluate the effect of pazopanib on QTc intervals. Two of the 63 patients had QTcF (corrected QT by the Fridericia method) >500 msec and three patients had an increase in QTcF >60 msec from baseline. [See Warnings and Precautions .]
Absorption: Pazopanib is absorbed orally with median time to achieve peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in geometric mean AUC and Cmax of 1,037 hrâ€¢Î¼g/mL and 58.1 Î¼g/mL (equivalent to 132 Î¼M), respectively. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.
Administration of a single pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax by approximately 2 fold and decreased tmax by approximately 2 hours compared to administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets of VOTRIENT should not be crushed.
Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal [see Dosage and Administration].
Distribution: Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 Î¼g/mL. In vitro studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).
Metabolism: In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.
Elimination: Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for <4% of the administered dose.
Hepatic Impairment: Interim data from a dose escalation study assessed the influence of hepatic impairment on the safety and pharmacokinetics of pazopanib in cancer patients with normal hepatic function and in patients with mild, moderate, and severe hepatic impairment. The starting doses were 800, 400, 200, and 100 mg once daily for patients with normal hepatic function and patients with mild, moderate, and severe hepatic impairment, respectively.
Pharmacokinetic data from patients with normal hepatic function (n = 12) and moderate (n = 7) hepatic impairment indicate that pazopanib clearance was decreased by 50% in those with moderate hepatic impairment. The maximum tolerated pazopanib dose in patients with moderate hepatic impairment is 200 mg once daily. There are no data on patients with mild or severe hepatic impairment. [See Use in Specific Populations .]
Drug Interactions: Coadministration of oral pazopanib with CYP3A4 inhibitors has resulted in increased plasma pazopanib concentrations. Concurrent administration of a single dose of pazopanib eye drops with the strong CYP3A4 inhibitor and Pgp inhibitor, ketoconazole, in healthy volunteers resulted in 220% and 150% increase in mean AUC(0-t) and Cmax values, respectively. [See Dosage and Administration and Drug Interactions (7.1).]
Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, Pgp, and BCRP, with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg pazopanib alone.
In vitro studies with human liver microsomes showed that pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and Cmax, respectively. [See Drug Interactions .]
In vitro studies also showed that pazopanib inhibits UGT1A1 and OATP1B1 with IC50s of 1.2 and 0.79 Î¼M, respectively. Pazopanib may increase concentrations of drugs eliminated by UGT1A1 and OATP1B1.
Pazopanib can increase serum total bilirubin levels [see Warnings and Precautions .]. In vitro studies showed that pazopanib inhibits UGT1A1, which glucuronidates bilirubin for elimination. A pooled pharmacogenetic analysis of 236 Caucasian patients evaluated the TA repeat polymorphism of UGT1A1 and its potential association with hyperbilirubinemia during pazopanib treatment. In this analysis, the (TA)7/(TA)7 genotype (UGT1A1*28/*28) (underlying genetic susceptibility to Gilbert's syndrome) was associated with a statistically significant increase in the incidence of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC).
Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.
Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC).
Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.