Jennie van Dyk 1, Tiziana Masini 2, Saba Lambert 3, Vivek Lal 4, Roeland Wasmann 1
1 Division of Clinical Pharmacology, Department of Medicine, University Of Cape Town (Cape Town, South Africa), 2 Global Accelerator for Paediatric formulations, Science for Health Department, World Health Organization (Geneva, Switzerland), 3 Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (London, United Kingdom), 4 Global Leprosy Programme, World Health Organization (Geneva, Switzerland)
Introduction
Leprosy remains an important cause of morbidity among children in vulnerable settings. Treatment consists of a 6- to 12-month multidrug therapy (MDT) course with rifampicin, dapsone, and clofazimine. The World Health Organization (WHO) supplies two types of pre-packed MDT blister packs free-of-charge to support treatment of adults and adolescents aged 10 to 14 years, respectively [1]. For children under 10 years, no specific blister pack exists, and dosing guidance is available but operationally challenging. In this group, WHO recommends mg/kg dosing using standalone formulations, which is poorly aligned with fixed-strength formulations and difficult to implement in routine care.
From a pharmacokinetic perspective, linear mg/kg dosing does not account for the nonlinear relationship between body size and drug clearance and may underexpose smaller children [2]. Dosing using harmonized weight bands is a more physiologically appropriate and programmatically feasible alternative [3]. Paediatric pharmacodynamic targets for leprosy are unavailable, and pharmacokinetic data in young children are sparse. For antibiotics, modelling-and-simulation–based extrapolation using adult-equivalent systemic exposure provides a pragmatic strategy for paediatric dose selection [2,4].
We therefore conducted a simulation study to develop harmonised, weight-banded MDT dosing strategies for young children and explore dose delivery using existing WHO MDT blister packs.
Methodology
The WHO paediatric dosing tool [2] was used to simulate rifampicin, clofazimine, and dapsone doses across harmonised WHO paediatric weight bands [3]. The tool incorporates allometric scaling and maturation functions to simulate adult-equivalent exposures. In this analysis, full maturation of clearance was assumed consistent with the epidemiology of leprosy, which is rarely observed in children below two years of-age.
Target pharmacokinetic exposure was steady-state area-under-concentration–time curve (AUCss) achieved in a 60-kg adult receiving standard leprosy MDT. Paediatric target exposures were set at 80–125% of the adult reference AUCss [5]. Additional simulations were performed using WHO paediatric tuberculosis regimens for rifampicin and clofazimine [6], and current leprosy protocols in children. These provided pragmatic upper thresholds for acceptable paediatric exposures. Candidate weight-banded regimens were iteratively simulated and assessed against adult-equivalence and paediatric reference exposure criteria.
Results
The following weight banded doses achieved adult-equivalent exposures across most weight bands:
• 6–14.9kg: rifampicin 150mg monthly; clofazimine 100mg monthly plus 50mg twice weekly; dapsone 50mg on alternate days.
• 15–24.9kg: rifampicin 300mg monthly; clofazimine 150mg monthly plus 50mg on alternate days; dapsone 50mg daily.
• 25–34.9kg: rifampicin 450mg monthly; clofazimine 150mg monthly plus 50mg on alternate days; dapsone 50mg daily (standard 10–14-year regimen).
Monthly rifampicin exposures remained far below exposure levels expected from daily rifampicin therapy for tuberculosis meningitis (160–220% adult leprosy exposure). For children weighing 13–14.9kg, rifampicin exposure was ~75% of adult reference, a modest reduction that did not justify dose escalation to 300mg.
Total monthly clofazimine exposures remained well below expected from second-line clofazimine used in multidrug-resistant tuberculosis (140–340% adult leprosy exposure) and declined below 80% adult-equivalent levels in children weighing >30 kg. This was considered acceptable, as these represent the highest paediatric doses before transition to the standard adult regimen and are equivalent to those received in children above 10 years of the same weight currently receiving this treatment.
For dapsone, exposures under the proposed regimens were comparable to current 25 mg once-daily dosing in children weighing 6–<15kg (75–140% adult-equivalent exposure). The existing 10–14-year MDT blister pack can be used to deliver the proposed doses in children under 10 years. Children weighing 25–39.9kg can use it as-is, while those weighing 6–24.9kg can be dosed by removing tablets according to two weight-band adjustment scenarios (6–14.9kg and 15–24.9kg), as defined in the developed guide. Conclusion Using the WHO paediatric dosing tool, we developed weight-banded MDT dosing strategies for children under 10 years-of-age with leprosy. The proposed regimens achieved adult-equivalent systemic exposures and remained within ranges expected from paediatric dosing used in clinical practice, while being deliverable using existing WHO MDT blister packs with minimal modification. Future leprosy management strategies could transition to a fully weight-banded approach, which better aligns with allometry-driven drug exposures at these ages and simplifies treatment. This work highlights the value of model-informed approaches for guideline optimisation in neglected paediatric populations where clinical data are limited and exposure-based pharmacodynamic targets are unavailable References: [1] Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. New Delhi: World Health Organization; 2018. [2] Denti P, Wasmann RE, Francis J, McIlleron H, Sugandhi N, Cressey TR, et al. One dose does not fit all: revising the WHO paediatric dosing tool to include the non-linear effect of body size and maturation. Lancet Child Adolesc Health 2022;6:9–10. https://doi.org/10.1016/S2352-4642(21)00302-3. [3] Waalewijn H, Almett M, Wasmann RE, Cressey TR, Easterbrook P, Olumese PE, et al. Simplifying medicine dosing for children by harmonising weight bands across therapeutic areas. Lancet Child Adolesc Health 2025;9:274–82. https://doi.org/10.1016/S2352-4642(25)00025-2. [4] European Medicines Agency. ICH E11A Guideline on pediatric extrapolation. 2024. [5] European Medicines Agency. Guideline on the investigation of bioequivalence. London: European Medicines Agency; 2010. [6] World Health Organization. Module 5: Management of tuberculosis in children and adolescents WHO operational handbook on tuberculosis. WHO operational handbook on tuberculosis, Geneva: 2022.
Reference: PAGE 34 (2026) Abstr 12284 [www.page-meeting.org/?abstract=12284]
Poster: Drug/Disease Modelling - Paediatrics