N. Azzopardi, S. Dupuis-Girod, D. Ternant, F.Faure, G. Paintaud.
CNRS - UMR 7292 (GICC)
Context: Hereditary Haemorrhagic Telangiectasia (HHT) is a genetic disorder of the blood vessels, which affects approximately 1 in 5,000 people. Patients with HHT suffer from unpredictable, recurrent, severe nasal bleeding which requires emergency care, nasal packing, blood transfusions, and invasive procedures. Anti-vascular endothelial growth factor (VEGF) drugs, such as bevacizumab, were previously shown to be effective in HHT.
Objectives: To describe the relationship between bevacizumab pharmacokinetics, VEGF concentrations and the reduction of the number of epistaxis episodes in HHT.
Methods: This study was a single-center, phase II trial. Seventeen HHT patients were administered 6 infusions of bevacizumab 5 mg/kg every 14 days. The total duration of the treatment was 2.5 months. Patients were followed up for 6 months after the beginning of bevacizumab treatment. Concentrations of bevacizumab and total VEGF were measured over time. Bevacizumab concentrations were described using a two-compartment model with first-order elimination. Concentrations of free and bound VEGF were described using a semi-mechanistic model. Free VEGF production and elimination are described by zero-order (kin) and first-order (kout) constants, respectively. Bevacizumab binds to free VEGF with a second-order constant (kon). Bevacizumab-VEGF complex is assumed to be totally eliminated with a first order constant (kdeg). In addition, the probability of daily epistaxis episodes was described using a Poisson model, which parameter (lambda) was influenced by bevacizumab pharmacokinetics. An effect compartment was used. A population approach was applied using MONOLIX 4.1.2.
Results: A total of 230 and 140 blood samples were available for analysis of bevacizumab and total VEGF concentrations, respectively. Population values for PK-PD parameters (interindividual CV%) were: central volume of distribution (V1) = 3.0 L (11%), elimination clearance (CL) = 0.17 L/day (24%), peripheral volume of distribution (V2) = 2.0 L (50%), distribution clearance (Q) = 0.44 L/day (25%), kin = 0.0026 µM/day (47%), kout = 0.29 1/day (78%), kon = 0.12 1/µM/day (61%) and kdeg = 0.17 1/day (26%), ke0 = 0.00048 1/day (194%), lambda0 = 0.46 (114%), IC50 = 3.7 mg/L (170%).
Conclusions: In this preliminary study of patients with HHT, short treatment of bevacizumab was associated with a long-lasting reduced number of episodes of epistaxis.
Trial registration: clinicaltrials.gov Identifier: NCT00843440.
Reference: PAGE 21 () Abstr 2604 [www.page-meeting.org/?abstract=2604]
Poster: Other Drug/Disease Modelling