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)-a and -P, 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-P 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 in a randomized, blinded, parallel study (N = 96) using moxifloxacin as a positive control. Pazopanib 800 mg was dosed under fasting conditions on Days 2 to 8 and 1,600 mg was dosed on Day 9 after a mea1 in order to increase exposure to pazopanib and its metabolites. No large changes (i.e., > 20 msec) in QTc interval following the treatment of pazopanib were detected in this QT study. The study was not able to exclude small changes ( < 10 msec) in QTc interval, because assay sensitivity below this threshold ( < 10 msec) was not established in this study. [See WARNINGS AND PRECAUTIONS.]
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 hr·μg/mL and 58.1 μg/mL (equivalent to 132 μM), 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].
Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 μg/mL. In vitro studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).
In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.
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.
Mild hepatic impairment was defined as either total bilirubin WNL with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of the ALT value. The median steady-state pazopanib Cmax and AUC(0.24) after a once daily dose of 800 mg/day in patients (N = 12) with mild impairment were 34 μg/ml (range 11 to 104) and 774 μg•hr/ml (range 215 to 2,034), respectively. These were in a similar range as the median steady-state pazopanib Cmax and AUC(0.24) in patients (N = 18) with no hepatic impairment (52 ng/ml, range 17 to 86 and 888 μg•hr/ml, range 346 to 1,482, respectively) [see DOSAGE AND ADMINISTRATION].
Moderate hepatic impairment was defined as total bilirubin > 1.5 X to 3 X ULN regardless of the ALT value. The maximum tolerated pazopanib dose in patients with moderate impairment was 200 mg once daily. The median (N = 11) steady-state Cmax with that regimen was 22 μg/ml (range 4.2 to 33), and the median AUC(0-24) was 257 μg•hr/ml (range 66 to 488). These values were approximately 43% and 29% those of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function (N = 18) [see DOSAGE AND ADMINISTRATION].
Severe hepatic impairment was defined as total bilirubin > 3 X ULN regardless of the ALT value. Median exposures in patients with severe hepatic impairment receiving 200 mg once daily (N=14) were unexpectedly lower than those observed in patients with moderate hepatic impairment receiving 200 mg once daily. The median steady-state Cmax was 9.4 μg/ml (range 2.4 to 24), and the median AUC(0-24) was 131 μg•hr/ml (range 47 to 473). These values were approximately 18% and 15% that of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function. Despite the observed concentrations, the dose of 200 mg was not well tolerated in patients with severe hepatic impairment. Use of VOTRIENT is not recommended in patients with severe hepatic impairment. [See Use In Specific Populations.]
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.]
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 μM, 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.
The safety and efficacy of VOTRIENT in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study. Patients (N = 435) with locally advanced and/or metastatic RCC who had received either no prior therapy or one prior cytokine-based systemic therapy were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo once daily. The primary objective of the study was to evaluate and compare the 2 treatment arms for progression-free survival (PFS); the secondary endpoints included overall survival (OS), overall response rate (RR), and duration of response.
Of the total of 435 patients enrolled in this study, 233 patients had no prior systemic therapy (treatment-naive subgroup) and 202 patients received one prior IL-2 or INFa-based therapy (cytokine-pretreated subgroup). The baseline demographic and disease characteristics were balanced between the VOTRIENT and placebo arms. The majority of patients were male (71%) with a median age of 59 years. Eighty-six percent of patients were Caucasian, 14% were Asian and less than 1% were other. Forty-two percent were ECOG performance status 0 and 58% were ECOG performance status 1. All patients had clear cell histology (90%) or predominantly clear cell histology (10%). Approximately 50% of all patients had 3 or more organs involved with metastatic disease. The most common metastatic sites at baseline were lung (74%), lymph nodes (56%), bone (27%), and liver (25%).
A similar proportion of patients in each arm were treatment-naive and cytokine- pretreated (see Table 3). In the cytokine-pretreated subgroup, the majority (75%) had received interferon-based treatment. Similar proportions of patients in each arm had prior nephrectomy (89% and 88% for VOTRIENT and placebo, respectively).
The analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire study population.
Efficacy results are presented in Table 3 and Figure 1.
Table 3: Efficacy Results by Independent Assessment
|Endpoint/Study Population||VOTRIENT||Placebo||HR (95% CI)|
|Overall ITT||N = 290||N = 145|
|Treatment-naive subgroup||N = 155
|N = 78
|Cytokine pre-treated subgroup||N = 135 (47%)||N = 67
|Response Rate (CR + PR) % (95% CI)||N = 290
30 (25.1, 35.6)
|N = 145
3 (0.5, 6.4)
|Duration of response Median (weeks) (95% CI)||58.7
|HR = Hazard Ratio; ITT = Intent to Treat; PFS =
Progression-free Survival; CR = Complete Response; PR = Partial Response
a P value < 0.001
b There were only 5 objective responses.
At the protocol-specified final analysis of OS, the median OS was 22.9 months for patients randomized to VOTRIENT and 20.5 months for the placebo arm [HR = 0.91 (95% CI: 0.71, 1.16)]. The median OS for the placebo arm includes 79 patients (54%) who discontinued placebo treatment because of disease progression and crossed over to treatment with VOTRIENT. In the placebo arm, 95 (66%) patients received at least one systemic anti-cancer treatment after progression compared to 88 (30%) patients randomized to VOTRIENT.
Figure 1: Kaplan-Meier Curve for Progression-Free
Survival by Independent Assessment for the Overall Population (Treatment-Naive
and Cytokine Pre-Treated Populations)
Last reviewed on RxList: 4/4/2012
This monograph has been modified to include the generic and brand name in many instances.
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