Pazopanib for the treatment of metastatic renal cell carcinoma

Amy Pick, Kelly K. Nystrom

Research output: Contribution to journalReview article

40 Citations (Scopus)

Abstract

Background: Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi-tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC. Objective: The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC. Methods: MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000-January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial. Results: Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t 1/2 of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P <0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin. Conclusions: Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.

Original languageEnglish
Pages (from-to)511-520
Number of pages10
JournalClinical Therapeutics
Volume34
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Renal Cell Carcinoma
Therapeutics
pazopanib
Clinical Trials
Protein-Tyrosine Kinases
Pharmacokinetics
United States Food and Drug Administration
Tablets
Disease-Free Survival
Meals
Platelet-Derived Growth Factor Receptors
Vascular Endothelial Growth Factor Receptor
Kidney Neoplasms
Anorexia
Aspartate Aminotransferases
Alanine Transaminase
Drug Interactions
Bilirubin

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pazopanib for the treatment of metastatic renal cell carcinoma. / Pick, Amy; Nystrom, Kelly K.

In: Clinical Therapeutics, Vol. 34, No. 3, 03.2012, p. 511-520.

Research output: Contribution to journalReview article

Pick, Amy ; Nystrom, Kelly K. / Pazopanib for the treatment of metastatic renal cell carcinoma. In: Clinical Therapeutics. 2012 ; Vol. 34, No. 3. pp. 511-520.
@article{aaaf5dd61a7a43608da75cef6b5f0e63,
title = "Pazopanib for the treatment of metastatic renal cell carcinoma",
abstract = "Background: Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi-tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC. Objective: The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC. Methods: MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000-January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial. Results: Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t 1/2 of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P <0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin. Conclusions: Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.",
author = "Amy Pick and Nystrom, {Kelly K.}",
year = "2012",
month = "3",
doi = "10.1016/j.clinthera.2012.01.014",
language = "English",
volume = "34",
pages = "511--520",
journal = "Clinical Therapeutics",
issn = "0149-2918",
publisher = "Excerpta Medica",
number = "3",

}

TY - JOUR

T1 - Pazopanib for the treatment of metastatic renal cell carcinoma

AU - Pick, Amy

AU - Nystrom, Kelly K.

PY - 2012/3

Y1 - 2012/3

N2 - Background: Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi-tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC. Objective: The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC. Methods: MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000-January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial. Results: Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t 1/2 of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P <0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin. Conclusions: Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.

AB - Background: Renal cell carcinoma (RCC) is the most common cancer in the kidneys. Until 2005, treatment options were limited to immunotherapy. Since that time, there have been numerous targeted therapy agents approved with improved efficacy toward RCC. Pazopanib is a multi-tyrosine kinase inhibitor that was approved by the US Food and Drug Administration in October 2009 and by the European Medicines Agency in June 2010 for the treatment of metastatic RCC. Objective: The objective of this report was to review pazopanib's mechanism of action; pharmacologic, pharmacokinetic, and dynamic properties; potential drug interactions; and the results of clinical trials evaluating efficacy and tolerability associated with pazopanib for the treatment of RCC. Methods: MEDLINE, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and therapeutic reviews (publication dates: 2000-January 1, 2012). Abstracts from the 2000 to 2011 meetings of the American Society of Clinical Oncology were searched for an updated safety profile and tolerability data of pazopanib in RCC. References from relevant articles were reviewed. Key search terms included pazopanib, Votrient, GW786034, renal cell carcinoma, adverse events, pharmacology, pharmacokinetic, and clinical trial. Results: Two clinical trials met the inclusion criteria for the use of pazopanib in RCC (a Phase II and a Phase III trial). Pazopanib is an inhibitor of numerous tyrosine kinases, including vascular endothelial growth factor receptor and platelet-derived growth factor receptors. It is involved in inhibiting signaling pathways, angiogenesis, and cell proliferation. Pazopanib was approved by the US Food and Drug Administration and the European Medicines Agency at the dose of 800 mg daily. Peak concentrations are achieved within 2 to 4 hours of this dose with a mean t 1/2 of 35 hours. The pharmacokinetic properties of pazopanib are affected by food as well as by crushing the tablet. A 2-fold increase in AUC was seen when pazopanib was administered with a high-fat meal as well as when crushing the tablet. Thus, pazopanib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Pazopanib is primarily metabolized by cytochrome P-450 3A4, and caution should be used with concomitant administration of cytochrome P-450 inducers and/or inhibitors. In a Phase III trial of pazopanib in metastatic RCC, pazopanib reportedly improved progression-free survival from a median of 4.2 to 9.2 months compared with placebo (P <0.0001). The most common adverse effects of pazopanib were hypertension, hair depigmentation, diarrhea, nausea, anorexia, and vomiting. Many of the grade 3/4 toxicities were hepatic in nature, with elevations occurring in aspartate aminotransferase, alanine aminotransferase, and bilirubin. Conclusions: Pazopanib is reportedly effective in the treatment of metastatic RCC. Although there are currently no direct comparisons between pazopanib and other tyrosine kinase inhibitors, the data suggest that pazopanib may be a first-line option in the treatment of RCC. The only Phase III trial of pazopanib suggests improvement of progression-free survival in RCC as well as tolerability in the selected population.

UR - http://www.scopus.com/inward/record.url?scp=84858609640&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858609640&partnerID=8YFLogxK

U2 - 10.1016/j.clinthera.2012.01.014

DO - 10.1016/j.clinthera.2012.01.014

M3 - Review article

VL - 34

SP - 511

EP - 520

JO - Clinical Therapeutics

JF - Clinical Therapeutics

SN - 0149-2918

IS - 3

ER -