Abstract
BackgroundPazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort.Patients and methodsRenal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed.ResultsSixty-one patients were included, of which 16.4% were underexposed (mean Cmin < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis Cmin > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis.ConclusionThis study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.
Highlights
Pazopanib is an angiogenesis inhibitor, targeting the vascular endothelial growth factor receptor (VEGFR)-1,2,3, platelet derived growth factor receptor (PDGFR) α/β, fibroblast growth factor receptor and the stem cell receptor/ c-Kit [1, 2].Pazopanib increased progression free survival in renal cell carcinoma and in soft tissue sarcoma compared to placebo, resulting in market approval for both tumor types by the Food and Drug Administration and European Medicine Agency [3, 4]
This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate
From April 2013 to November 2016, 61 patients were included in the analysis, of whom 35 had renal cell carcinoma and 26 soft tissue sarcoma
Summary
Pazopanib increased progression free survival in renal cell carcinoma and in soft tissue sarcoma compared to placebo, resulting in market approval for both tumor types by the Food and Drug Administration and European Medicine Agency [3, 4]. Pazopanib has a complex pharmacokinetic profile, described by low, non-linear and time-dependent bioavailability and large inter-individual variability [6,7,8,9]. This results in a subset of patients receiving less than optimal exposure [5]. Conclusion This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Conclusion This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate
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