Yuanxi Zou (1), Megan Palmer (2), Anneke Hesseling (2), Mats O Karlsson (1), Paolo Denti (3), Anthony J. Garcia-Prats (2,4), Elin M Svensson (1,5)
1) Department of Pharmacy, Uppsala University, Uppsala, Sweden 2) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University 3) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa 4) Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA 5) Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
Objectives: Moxifloxacin, a fluoroquinolone antibiotic, is a priority drug for the treatment of rifampicin-resistant tuberculosis (RR-TB). The standard 400 mg tablet formulation is poorly palatable and non-dispersible, posing difficulties for accurate dosing in young children. It has been previously reported that pediatric exposures are substantially lower than in adults given the World Health Organization (WHO) recommended doses. A new 100 mg moxifloxacin dispersible tablet formulation has recently been developed for better use in children. We assessed the pharmacokinetics (PK) of this new dispersible formulation of moxifloxacin against the standard tablet formulation in children treated for RR-TB and evaluated the dosing recommendations for moxifloxacin in children.
Methods: The CATALYST study was an open-label multisite trial of the PK, safety, tolerability, and acceptability of new child-friendly formulations of TB drugs including moxifloxacin. Participants <15 years treated for RR-TB <16 weeks, were enrolled in South Africa, India, and the Philippines. All participants underwent a first PK visit (PK1) while taking the standard 400 mg tablet formulation, then switched to the new 100 mg dispersible formulation at the second PK visit (PK2) after PK1, both following WHO-guided dosing. At each PK visit, six blood samples were drawn over 24h.
PK data were analyzed in NONMEM with FOCE-I estimation. The starting model was a PK model previously developed by Radtke et.al. from children with RR-TB.1 Covariates tested for significance at p<0.05 included formulation type, metabolic maturation with age, HIV status, and nutritional measures. The final model was evaluated through visual predictive checks (VPC) and non-compartment analysis posterior predictive checks (ncappc). To compare with the standard bioequivalence criterion of 80-125%, a 90% confidence interval (CI) of the formulation effect on bioavailability was obtained with log-likelihood profiling (LLP) using PsN. In the final model, 95% CIs of the estimates were obtained with sampling importance resampling (SIR) using PsN.2 Simulations were made to evaluate the current WHO pediatric dosing and a previously proposed alternative higher dosing (Radtke dosing) by comparing the area under concentration (AUC0-24) with adult value and max concentration (Cmax) for safety.1,3 The reference value was summarised by weighting several adult PK studies for the standard dose 400 mg daily, i.e., AUC0-24 with a median of 37 mg·h/L, ranging 15-76 mg·h/L as 95% population coverage, while maintaining Cmax under max reported value 10 mg/L in adult studies.
Results: Thirty-six children were enrolled with 16 <15 kg and 7 <2 years. In total, 434 observations were obtained. The final model was a two-compartment model with first-order elimination. Compared with the starting model, transit compartment number increased from 1 to 3 to better capture the absorption described by mean absorption time (MAT); interoccasion variability was introduced to the model and on bioavailability and MAT to account for multiple dosing occasions in the study. Interindividual variability was included on clearance. All disposition parameters were allometrically scaled using weight with fixed theoretical factors. No other covariate was found significant.
The new formulation was not significantly different in bioavailability or MAT. The estimated bioavailability ratio of the new to standard formulations was 105 (LLP-CI, 95-115) %, fulfilling the preset criterion. With the final model, the dosing simulation showed that the current WHO pediatric dosing yielded exposures similar to the summarised adult level for children >10kg, but lower exposures in the smallest children. The Radtke doses were predicted to generate relatively high exposures compared to the summarised adult level.
Conclusions: The new 100 mg dispersible formulation of moxifloxacin has similar PK to the standard 400 mg non-dispersible formulation in children with RR-TB across three countries. The findings support the use of the new formulation of moxifloxacin in children. Simulations with our updated model suggest that the current WHO-recommended doses of moxifloxacin for children with RR-TB provide exposures similar to the summarised adult level for most children, but those below 10 kg may benefit from increased doses.
References:
This project is made possible thanks to Unitaid’s funding and support, through the BENEFIT Kids project. Unitaid accelerates access to innovative health products and lays the foundations for their scale-up by countries and partners.
[1] Radtke KK, Hesseling AC, Winckler JL, et al. Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children. Clinical Infectious Diseases. 2022;74(8):1372-1381. doi:10.1093/cid/ciab641
[2] Dosne AG, Bergstrand M, Karlsson MO. An automated sampling importance resampling procedure for estimating parameter uncertainty. J Pharmacokinet Pharmacodyn. 2017;44(6):509-520. doi:10.1007/S10928-017-9542-0/FIGURES/6
[3] World Health Organization. Operational Handbook on Tuberculosis – Module 5: Management of Tuberculosis in Children and Adolescents.; 2022.
Reference: PAGE 32 (2024) Abstr 11025 [www.page-meeting.org/?abstract=11025]
Poster: Drug/Disease Modelling - Paediatrics