Sean Oosterholt (1,2), Oscar Della Pasqua (2)
(1) Clinical Pharmacology & Therapeutics, UCL School of Life and Medical Sciences, London, UK, (2) GlaxoSmithKline, London, United Kingdom
Objectives: Raxibacumab is a fully humanised monoclonal antibody that blocks the protective antigen-receptor interaction of B. anthracis, thereby protecting target cells from PA binding to anthrax toxin receptors. Ultimately, this mechanism preserves host cells from anthrax toxin mediated effects. Raxibacumab, is currently approved in the USA for individuals exposed to inhaled anthrax, who are symptomatic of the infection. The aim was to review the dose rationale for raxibacumab in children taking into account the contribution of maturation and other age-related differences in drug disposition.
Methods: Rich pharmacokinetic data from three different trials in healthy adult subjects were analysed, yielding a pool of 322 subjects (age: 39 ±15, body weight: 76.9 ±117.4). The analysis was performed using a non-linear mixed effects modelling approach. Final parameter estimates were used to extrapolate drug disposition from adults to children. Simulation scenarios included the effect of changes in pharmacokinetics due to physiological growth, maturation and a combination of both factors. Predicted AUC, Cmax and T >Cmax were used as parameters of interest for the purposes of this analysis. Dose recommendations for children from birth to < 18 years of age were derived taking into account the observed exposure to raxibacumab in adults and pre-clinical efficacy experiments.
Results: The PK of raxibacumab after intravenous administration of a 40 mg/kg dose was best described by a two-compartment model with first order absorption and elimination. There was no accumulation, metabolic inhibition, or induction observed during the course of treatment. Body weight was found to be a significant covariate on clearance, volume of distribution, inter-compartmental clearance and peripheral volume. Simulations showed that a combination of allometric scaling and maturation function reflected the most likely scenario in young children, with changes in drug disposition leading to an increase in drug levels > 2 times the maximum exposure observed in adults.
Conclusion: Given the nature of the infection, extrapolation is the only method available to explore the dose rationale for this vulnerable population. Extrapolations showed that the use of a weight-banded dosing regimen accounts for the most likely physiological changes in the disposition of raxibacumab, with doses ranging from 75 mg/kg in children with body weight < 1.5 kg to 40 mg/kg in patients with body weight > 50 kg.
Reference: PAGE 25 (2016) Abstr 6017 [www.page-meeting.org/?abstract=6017]
Poster: Drug/Disease modeling - Paediatrics