Pharmacokinetics of pazopanib administered in combination with bevacizumab
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- 作者：Diane-Charlotte Imbs (1)
Sylvie Négrier (2)
Philippe Cassier (2)
Antoine Hollebecque (3)
Andrea Varga (3)
Ellen Blanc (2)
Thierry Lafont (1)
Bernard Escudier (3)
Jean-Charles Soria (3)
David Pérol (2)
Etienne Chatelut (1) - 关键词：Tyrosine kinase inhibitors ; Pharmacokinetic ; pharmacodynamic relationships ; Population pharmacokinetics ; Drug interaction
- 刊名：Cancer Chemotherapy and Pharmacology
- 出版年：2014
- 出版时间：June 2014
- 年：2014
- 卷：73
- 期：6
- 页码：1189-1196
- 全文大小：
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Sylvie Négrier (2)
Philippe Cassier (2)
Antoine Hollebecque (3)
Andrea Varga (3)
Ellen Blanc (2)
Thierry Lafont (1)
Bernard Escudier (3)
Jean-Charles Soria (3)
David Pérol (2)
Etienne Chatelut (1)
1. EA4553 Institut Claudius-Regaud, Université de Toulouse, 20, rue du Pont-Saint-Pierre, 31052, Toulouse, France
2. Centre Léon-Bérard, Lyon, France
3. Institut Gustave Roussy, Villejuif, France - ISSN：1432-0843
文摘
A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2?weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600?mg) at Day 1 (given alone) and Day 15 (the day of the 7.5?mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60?L/h) presented an inter-individual variability of 40?%, and an inter-occasion of 27?%. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (?6.4, 95?% confidence interval of ?.5 to ?7.2?%). However, trough pazopanib concentrations observed at Day 16 (24?h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600?mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.