Diane-Charlotte Imbs1,2, Marie-Noelle Paludetto1,2, Sylvie Négrier3, Helen Powell4, Thierry Lafont1,2, Melanie White-Koning2, Etienne Chatelut5,6, Fabienne Thomas1,2. 1. Department of Pharmacology, Institut Claudius-Regaud, IUCT-Oncopole, 1, avenue Irène Joliot-Curie, Toulouse, F-31059, France. 2. EA4553 Université Toulouse III Paul-Sabatier, Toulouse, France. 3. Centre Léon-Bérard, Lyon, France. 4. Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. 5. Department of Pharmacology, Institut Claudius-Regaud, IUCT-Oncopole, 1, avenue Irène Joliot-Curie, Toulouse, F-31059, France. chatelut.etienne@iuct-oncopole.fr. 6. EA4553 Université Toulouse III Paul-Sabatier, Toulouse, France. chatelut.etienne@iuct-oncopole.fr.
Abstract
INTRODUCTION: Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process. METHODS: An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancer patients treated daily with pazopanib. RESULTS: We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 ± 0.0013 % at 40 μg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 μg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to α1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 ± 0.0022 %, 0.992 ± 0.44 % and 7.4 ± 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancer patients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia. CONCLUSIONS: Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity.
INTRODUCTION:Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process. METHODS: An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancerpatients treated daily with pazopanib. RESULTS: We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 ± 0.0013 % at 40 μg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 μg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to α1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 ± 0.0022 %, 0.992 ± 0.44 % and 7.4 ± 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancerpatients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia. CONCLUSIONS:Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancerpatients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity.
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