Skip to Main content Skip to Navigation
Master Thesis

Étude de la pharmacocinétique du pazopanib en association avec le cisplatine à partir de données issues d'un essai de phase I

Abstract : Aim. A phase I study combining daily oral pazopanib and cisplatin (given iv every three weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pharmacokinetic interactions between the two drugs were evaluated. Methods. Plasma pazopanib and ultrafiltrable cisplatin concentrations were obtained in 35 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib, and 60 or 75 mg/m² of cisplatin. Data were analyzed using the NONMEM program. Results. Maximum Tolerated Dose corresponded to 400 mg of pazopanib and 75 mg/m² of cisplatin. Mean (CV% for interindividual variability) cisplatin clearance was 13.6 L/h (27.4%) and not influenced by pazopanib. However, pazopanib pharmacokinetics were significantly modified by cisplatin treatment. Mean (CV%) of oral pazopanib clearance was 0.66 L/h (55%) at Day -1 (before cisplatin administration) and 24.8% lower at Day 1 (day of cisplatin administration), and 32.9% lower at Day 2 (after cisplatin administration). The interaction is likely due to competitive inhibition of pazopanib metabolism and efflux by aprepitant that was systematically combined to cisplatin. The plasma pazopanib exposures observed at Day -1 after administration of 400 mg were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800mg) during the first-in-man phase 1. Conclusion. The pazopanib overexposure observed likely contributed to the poor tolerance.
Document type :
Master Thesis
Complete list of metadata

Cited literature [60 references]  Display  Hide  Download

https://dumas.ccsd.cnrs.fr/dumas-01109493
Contributor : Bu Carreire Université de Bordeaux <>
Submitted on : Monday, January 26, 2015 - 2:18:40 PM
Last modification on : Wednesday, August 23, 2017 - 4:31:09 PM
Long-term archiving on: : Monday, April 27, 2015 - 10:30:40 AM

Identifiers

  • HAL Id : dumas-01109493, version 1

Collections

Citation

Diane-Charlotte Imbs. Étude de la pharmacocinétique du pazopanib en association avec le cisplatine à partir de données issues d'un essai de phase I. Sciences pharmaceutiques. 2014. ⟨dumas-01109493⟩

Share

Metrics

Record views

156

Files downloads

1033