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

Oosterholt, SP; Della Pasqua, O; (2021) Extrapolation and dosing recommendations for raxibacumab in children from birth to < 18 years of age. British Journal of Clinical Pharmacology 10.1111/bcp.14893. (In press).

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Abstract

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 < 10 kg, 45 mg/kg for individuals < 50 kg, 40 mg/kg for all 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.

Type: Article
Title: Extrapolation and dosing recommendations for raxibacumab in children from birth to < 18 years of age.
Location: England
DOI: 10.1111/bcp.14893
Publisher version: https://doi.org/10.1111/bcp.14893
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: clinical trial simulations, maturation function, dose rationale, paediatric extrapolation, population pharmacokinetics, raxibacumab
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10127807
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