title: Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.
abstract: 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 (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries.
  
  
  RESULTS
  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, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Salix Pharmaceuticals, Inc., 8510 Colonnade Center Drive Raleigh, NC 27615, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Ball
authors.affiliation: Pharmacology Department, Université de Bordeaux INSERM U657, 146 Leo Saignat, Bordeaux 33076, France.
authors.forename: M
authors.initials: M
authors.lastname: Molimard
authors.affiliation: GU Oncology Center of Excellence, Baylor University Medical Center, 3410 Worth Street, Dallas, TX 75246, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Hutson
authors.affiliation: 1] Salix Pharmaceuticals, Inc., 8510 Colonnade Center Drive Raleigh, NC 27615, USA [2] GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: C
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: D
authors.initials: D
authors.lastname: Rajagopalan
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: S
authors.initials: S
authors.lastname: Swann
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: R
authors.initials: R
authors.lastname: Amado
authors.affiliation: Salix Pharmaceuticals, Inc., 8510 Colonnade Center Drive Raleigh, NC 27615, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pandite
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001794:Blood Pressure; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D014018:Tissue Distribution; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2