Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors. - Archive ouverte HAL Access content directly
Journal Articles Cancer Chemotherapy and Pharmacology Year : 2013

Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors.

(1) , (2) , (3) , (3)
1
2
3

Abstract

OBJECTIVE: Aflibercept (Zaltrap®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. METHODS: Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. RESULTS: An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL(f)) and bound aflibercept (CL(b)) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V(p)) and bound (V(b)) aflibercept were similar (~4 L). CL f and V(p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL(f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. CONCLUSIONS: Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.
Fichier principal
Vignette du fichier
thai13_CCP_versionauteur.pdf (337.12 Ko) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

inserm-00881821 , version 1 (06-05-2014)

Identifiers

Cite

Hoai-Thu Thai, Christine Veyrat-Follet, France Mentré, Emmanuelle Comets. Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors.. Cancer Chemotherapy and Pharmacology, 2013, 72 (1), pp.167-80. ⟨10.1007/s00280-013-2182-1⟩. ⟨inserm-00881821⟩
332 View
643 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More