Sally Babiker (1), Umberto Villani (1,2), Andrea Logreco (1,3), Oscar Della Pasqua (1,2)
(1) Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom, (2) Istituto per le Applicazioni del Calcolo, Consiglio Nazionale delle Ricerche, Rome, Italy, (3) Agenzia Italiana del Farmaco (AIFA, Italian Medicine Agency), Rome, Italy
Objectives: At the forefront of the causes of death globally, multi-drug resistant (MDR) tuberculosis (TB) manifests severely in children, posing difficulties in achieving disease control[1,2]. In 2022, the World Health Organisation (WHO) made a conditional recommendation on the use of bedaquiline (BDQ), a novel mycobacterial ATP synthase inhibitor, to treat MDR-TB in all children[3]. Despite this optimistic advancement, the WHO guidelines cite that this recommendation is based on little certainty of evidence, highlighting the lack of pharmacokinetic (PK) data available on BDQ in children[4,5]. In fact, a recent observational clinical study in 15 children has shown that recommended BDQ doses in children ≥ 6 years old produced lower plasma concentrations compared to adults[6]. Understanding disposition differences in children is particularly important, as not only the lungs but also other tissues and organs are involved. Moreover, a considerable proportion of the population has HIV co-infection and are often exposed to efavirenz (EFV), a first line NNRTI. Accordingly, a dose rationale, leveraging available knowledge on developmental and allometric concepts is needed to ensure high probability of target attainment (PTA) and an acceptable safety profile to minimise the effect of the metabolite (M2) on QTc interval. Hence, this work aimed to utilise a model-based framework to identify optimised dosing regimens for BDQ in paediatric MDR-TB patients aged 2-17 years old.
Methods: A previously published population PK model[7] was adapted to support the extrapolation of the PK of BDQ and M2 from adults to children. The analysis was implemented assuming no differences in the underlying concentration-antibacterial activity relationship across populations. Allometric principles were considered, along with known covariate factors, as a basis for the extrapolation of disposition parameters in children. Employing a virtual cohort of adults (N=105, weight range 40.3kg-80kg) and paediatric patients (N=400, weight range 16kg-50kg), several dosing scenarios were simulated, starting from the current BDQ dosage in adults (400 mg q.d. for 2 weeks, then 200 mg thrice weekly for 22 weeks)[8]. The tested regimens only included options that could be implemented in the clinic with currently marketed BDQ formulations. NICE and South Africa (ZA) guidelines were used as reference for the analysis. Initially, AUC0-168h at week 2 and 24, as well as Cmax were used as criteria for optimisation of the regimens for BDQ and M2, respectively. In a second step, BDQ systemic exposures in paediatric TB/HIV patients treated with EFV were simulated considering the metabolic induction and changes in the clearance of both BDQ and M2[9].
Results: Our analysis strongly suggests that there is an opportunity for optimising BDQ-containing regimens in children from 2-17 years old. In line with current guidelines, a simplified weight-banded dosing regimen with 3 weight bands (16-20/20-30kg/30-50kg) was identified for children. Doses of 200/200/400 mg q.d. in the first 2 weeks should be followed by 100/100/200 mg thrice weekly for 22 weeks. The median (90%CI) week 2 and 24 AUC0‑168h and Cmax were 346.4(83.3-774) μg⋅h/mL, 166.5(29.2-436) μg⋅h/mL and 3.5(0.8-8) μg/mL for BDQ, and 89.1(11.3-244.6) μg⋅h/mL, 45.9(3.6-132.3) μg⋅h/mL and 0.6(0.1-1.6) μg/mL for M2, respectively. The proposed regimen ensures a higher probability of target attainment, especially in the lowest weight band, whilst minimising the risk of high M2 levels across the entire weight range. Indeed, such dose rationale featured a low proportion (5.25%) of patients above the 95th percentile of Cmax for M2 in adults and a higher proportion (70%) of patients above the 25th percentile of AUC0-168h for BDQ, as compared to regimens from NICE guidelines. Additionally, in case of co-administration of EFV and BDQ, a higher maintenance dose should be considered, namely, 150/200/300mg thrice weekly for 22 weeks.
Conclusions: The proposed regimens provide the basis for optimised antitubercular therapy, whilst minimising the proportion of paediatric patients who exceed reference ranges previously identified in adults. Notably, our work incorporates current understanding of the interaction between BDQ and EFV, ensuring the dose rationale for paediatric patients who are usually excluded from clinical trials due to HIV co-infection.
References:
[1] “Global Tuberculosis Report 2022,” Oct. 27, 2022.https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022
[2] S. T. Partnership, “Roadmap for childhood tuberculosis: towards zero deaths,” 2013. https://apps.who.int/iris/handle/10665/89506
[3] Report of a WHO expert consultation on dosing to enable implementation of treatment recommendations in the WHO consolidated guidelines on the management of TB in children and adolescents. (2022). https://www.who.int/publications/i/item/9789240055193.
[4] World Health Organisation (WHO), WHO Operational Handbook on Tuberculosis Module 5: Management of Tuberculosis in Children and Adolescents. 2022. [Online]. Available: https://iris.who.int/bitstream/handle/10665/352523/9789240046832-eng.pdf
[5] D. Dharmapalan and S. S. Mane, “Pediatric Drug-Resistant Tuberculosis: The Current and Future Prospects for Management and Prevention,” Pathogens, vol. 12, no. 11, p. 1372, Nov. 2023, doi: 10.3390/pathogens12111372.
[6] J. Hughes et al., “Pharmacokinetics and safety of bedaquiline in human immunodeficiency virus (HIV)-Positive and negative older children and adolescents with Rifampicin-Resistant tuberculosis,” Clinical Infectious Diseases, vol. 75, no. 10, pp. 1772–1780, Apr. 2022, doi: 10.1093/cid/ciac252.
[7] E. M. Svensson, A.-G. Dosne, and M. O. Karlsson, “Population Pharmacokinetics of bedaquiline and metabolite M2 in patients with Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and albumin,” CPT: Pharmacometrics & Systems Pharmacology, vol. 5, no. 12, pp. 682–691, Nov. 2016, doi: 10.1002/psp4.12147.
[8] European Medicines Agency, Sirturo, INN-bedaquiline. SUMMARY OF PRODUCT CHARACTERISTICS. 2023. [Online]. Available: https://www.ema.europa.eu/en/documents/product-information/sirturo-epar-product-information_en.pdf
[9] Svensson, E. M., Aweeka, F., Park, J. G., Marzan, F., Dooley, K. E., & Karlsson, M. O. (2013). Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrobial Agents and Chemotherapy, 57(6), 2780–2787. https://doi.org/10.1128/AAC.00191-13
Reference: PAGE 32 (2024) Abstr 11247 [www.page-meeting.org/?abstract=11247]
Poster: Methodology - Other topics