Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma

Background: 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). Methods: 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 (C tau) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at C tau decile boundaries. Results: Strong correlation between increased blood pressure and C tau was observed (r(2) = 0.91), whereas weak correlation was observed between C tau and decline from baseline in sVEGFR2 (r(2) = 0.27). C tau threshold of >20.5 mu g ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from C tau > 20.5 mu g ml(-1). However, the association of C tau with certain adverse events, particularly hand-foot syndrome, was continuous over the entire C tau range. Conclusions: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire C tau range. Monitoring C tau may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.