Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation.
OBJECTIVE
The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients.


METHODS
Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5-21 years), body weight (BWT; 5.9-125 kg), and regimens (5-15 mg kg(-1) biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady-state exposure was simulated under BWT-based, body surface area (BSA)-based, ideal body weight (IBW)-based, and tier-based doses. NONMEM and R were used for analyses.


RESULTS
Typical estimates of clearance, central volume of distribution (V1), and median half-life were 9.04 ml h(-1) , 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (C min) and 29% higher peak (Cmax) concentrations. BWT-adjusted clearance and V1 remained unchanged across ages. Paediatric C min was similar to adult C min under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier-based doses.


CONCLUSIONS
BWT-adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA-based, IBW-based, and tier-based doses offered no substantial advantage over the BWT-based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.
Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
Kelong
K
Han
Pharsight Consulting Services, Montreal, QC, Canada.
Thomas
T
Peyret
Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
Angelica
A
Quartino
Pharsight Consulting Services, Montreal, QC, Canada.
Nathalie H
NH
Gosselin
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC.
Sridharan
S
Gururangan
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Michela
M
Casanova
Department of Pediatric Oncology, Emma Children's Hospital-Academic Medical Center (EKZ-AMC), Amsterdam, The Netherlands.
Johannes H M
JH
Merks
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Maura
M
Massimino
Gustave Roussy, Faculté de Médecine, University Paris-SUD, Villejuif, France.
Jacques
J
Grill
Division of Pediatrics, MD Anderson Cancer Center, Houston, TX.
Najat C
NC
Daw
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
Fariba
F
Navid
Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
Jin
J
Jin
Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
David E
DE
Allison
D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D017410:Practice Guidelines as Topic; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab
bevacizumab; body surface area; central nervous system tumour; dosing strategy; external validation; paediatric