Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma
Open Access
- 28 October 2014
- journal article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 111 (10), 1909-1916
- https://doi.org/10.1038/bjc.2014.503
Abstract
Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 μg ml(-1) was associated with improved efficacy (PFS, P20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.Keywords
This publication has 30 references indexed in Scilit:
- Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumorsCancer Chemotherapy and Pharmacology, 2013
- Moving towards dose individualization of tyrosine kinase inhibitorsCancer Treatment Reviews, 2011
- Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III TrialJournal of Clinical Oncology, 2010
- Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell CarcinomaJournal of Clinical Oncology, 2010
- Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometryJournal of Chromatography B, 2009
- Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinomaExpert Opinion on Investigational Drugs, 2008
- Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteinsJournal of Translational Medicine, 2007
- Rapid vascular regrowth in tumors after reversal of VEGF inhibitionJCI Insight, 2006
- Role of vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 in the vasodilator response to vascular endothelial growth factor in the neonatal piglet lungCritical Care Medicine, 2005
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000