Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation

Abstract

Aim: 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.

Keywords: bevacizumab; body surface area; central nervous system tumour; dosing strategy; external validation; paediatric.

© 2015 Genentech Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

Weight‐adjusted pharmacokinetic (PK) parameters. (A) Clearance and (B) central volume of distribution obtained from the bevacizumab base model across age. LOESS, locally weighted scatterplot smoothing

Figure 2

(A) Prediction‐corrected visual predictive check for the serum concentration–time profiles of bevacizumab using the final model in paediatric cancer patients. (B) Section of (A) before day 35 after dose administration, where the majority (94%) of the data points lay. CI, confidence interval; Pred, population prediction

Figure 3

Impact of the variation for a single covariate included in the final model on steady‐state bevacizumab exposure in paediatric cancer patients. (A) Trough concentration (Cmin) and (B) peak concentration (Cmax). Red vertical lines represent the ‘base’, defined as the exposure of a typical patient – i.e. a 44‐kg female paediatric patient with an albumin level of 39 g l–1 and sarcomas. The dark blue‐shaded curve at the bottom, with a value at each end, shows the 5th to 95th percentile exposure range across the entire population. Each light blue‐shaded bar represents the influence of a single covariate on the steady‐state exposure after repeated bevacizumab doses of 10 mg kg–1 once every two weeks. The label at left end of the bar represents the covariate being evaluated. The upper and lower values for each covariate capture 90% of the plausible range in the population. The length of each bar describes the potential impact of that particular covariate on bevacizumab steady‐state exposure, with the percentage value in the parentheses at each end representing the percentage change in exposure from the ‘base’. The most influential covariate is at the bottom of the plot for each exposure metric, except for the body weight effect stratified by age group, which is displayed on the top. CI, confidence interval; Cmax, peak concentration; Cmin, trough concentration

Figure 4

External validation for (A) primary CNS tumours and (B) sarcomas. About 95% of the prediction‐corrected observations fall between the 95% prediction interval boundaries, which are very close to the observed 2.5th and 97.5th percentiles. CNS, central nervous system; PI, prediction interval

Figure 5

Simulated steady‐state bevacizumab exposure in paediatric patients under BWT‐, BSA‐, IBW‐, and tier‐based doses. Equivalent doses (once every 2 weeks) were used: 10 mg kg–1 for the BWT‐based dose, 398 mg m–2 for the BSA‐based dose, and 11 mg kg–1 for the IBW‐based dose. The tier‐based dose in each BWT range was determined so that the steady‐state area under the curve (AUC) under these doses matched the adult steady‐state AUC: 180 mg for <15 kg, 360 mg for 15 – 40 kg, 640 mg for >40 kg. Only patients with a BWT below 80 kg are displayed. BSA, body surface area; BWT, total body weight; Cmax, peak concentration; Cmin, trough concentration; IBW, ideal body weight; PI, prediction interval