Extrapolation and dosing recommendations for raxibacumab in children from birth to < 18 years of age.

Aim The US Food and Drug Administration's Animal Rule allows for the approval of drugs when human efficacy studies are not ethical. While the therapeutic doses of raxibacumab, a monoclonal antibody for the prophylaxis and treatment of inhalational anthrax, have been based on pharmacokinetic data from adult subjects, its disposition in children has not been evaluated in clinical trials. Here we evaluate the effect of demographic covariates on the pharmacokinetic disposition of raxibacumab and explore opportunities for the optimization of the paediatric doses. Methods A population pharmacokinetic model was used as basis for the extrapolation of raxibacumab disposition from adults to children. Different extrapolation scenarios, including weight-banded dosing regimens, were considered to assess the effect of growth and maturation processes on the pharmacokinetic parameters of interest. AUC, Cmax , and the time of serum raxibacumab concentrations greater than or equimolar to the highest serum protective antigen concentrations observed for at least 28 days in any monkey challenged with Bacillus anthracis that died were derived and compared with the currently approved US doses. Results Based on practical considerations, a weight-banded dosing regimen consisting of four dose levels (75 mg/kg for individuals ≤ 1.5 kg, 55 mg/kg for individuals 50 kg) was necessary to optimize target exposure across the paediatric population. Conclusion Age-related maturation processes may affect raxibacumab clearance in young patients. The proposed dosing regimens take into account effects of body weight and maturation processes on the elimination of raxibacumab.