Yuanxi Zou1, Megan Palmer2, Heather R Draper2, Anthony Garcia-Prats2,3, Anneke C Hesseling2, Mats O Karlsson1, Elin M Svensson1,4
1Department of Pharmacy, Uppsala University, 2Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, 3Department of Pediatrics, University of Wisconsin-Madison, 4Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center
Objectives Clofazimine (CFZ) and moxifloxacin (MFX) are commonly used in combination for rifampicin-resistant tuberculosis (RR-TB) treatment as recommended by the World Health Organization (WHO).¹ However, both drugs prolong QT interval by blocking the “hERG” potassium channel, increasing the risk of cardiac arrhythmias such as Torsades de Pointes.?² ³ We aimed to characterize the association between the pharmacokinetics (PK) of the two drugs and heart-rate-corrected QT measurements in children with RR-TB. Methods CATALYST was a multisite trial evaluating the PK and safety of MFX and CFZ in children <15 years routinely treated for RR-TB. At study entry, participants had been receiving MFX and CFZ for <16 weeks, with no restriction on concurrent treatment with bedaquiline (BDQ) and/or delamanid (DLM). Electrocardiograms (ECG) for safety monitoring with blood samples for PK analyses were collected at pre-dose, 2, and 8h post-dose during 2 intensive sampling visits at study initiation, and sparse collection at study weeks 16 (pre-dose), 20 (4h post-dose), and at 24 (pre-dose). Fridericia-corrected QT (QTcF) data were analysed using nonlinear mixed-effect modelling. Structural components were estimated, including baseline and exposure-response relationship (drug), while exploring time effect over the treatment and diurnal variation. The drug function incorporated predicted CFZ and MFX concentrations at each ECG measurement time using population PK models developed based on CATALYST data.4 Given the known QT-prolonging effects of metabolites of DLM (M1) and BDQ (M2) and the absence of their concentration data in CATALYST, simulated concentrations were used to account for their potential contribution to QT prolongation.5 6? The interindividual variabilities (IIV) of the involved structural parameters were tested assuming log-normal distribution. Covariates including age, sex, race, and country were tested on baseline and drug-effect parameters. Results Data from 36 children with 318 QT samples were analysed. The final PK-QTcF model included baseline, drug, time, and age effects. Baseline was estimated as 416 (95% confidence interval (CI) 407–425) ms with log-normally distributed IIV (3.2% of coefficient variation). Age significantly affected QTcF baseline via an Emax function, estimating typically 44 ms lower in newborns compared to 15-year-olds, reaching 50% of the difference at age 4.9 years. The model accounted for joint effects of CFZ, MFX, M1, and M2 using a pharmacodynamic interaction model.?7? As direct estimation was not possible due to lack of PK data, EC50 of M1 and M2 (concentration for 50% maximum effect, Emax) were fixed at previously published estimates of 205 and 695 ng/mL.8? A common Emax was shared among all four compounds, reflecting their common QT-prolonging mechanism. Due to lack of stable estimation, Emax was fixed at 25.9 ms, reported from the same model developed for M1 and M2.?8? The EC50 of CFZ and MFX were estimated at 2.12 (CI 0.552–8.86) and 4.7 (CI 1.22–13.3) mg/L, respectively. The time effect, describing the additional increase of QTcF since start of treatment, improved the model fit. It was included as a fixed function based on previous work due to unstable estimation: QTmax*(1-exp(-ln(2)/half_life*time[weeks])), QTmax=7.1 ms for max increase, half_life=7.5 weeks.?8? Other covariates were not included in the model due to lack of statistical significance. The final model was used to simulate QT prolongation over time after treatment, quantifying each compound’s contribution. Drug concentrations were simulated for a typical child in CATALYST receiving WHO doses over the observed treatment duration.?¹ The simulation showed that MFX was the primary contributor to QT prolongation at 2h post-dose aligning with its peak concentration, but did not contribute to the cumulative effects given its short half-life. The long half-life compounds CFZ, M2, and M1 drove prolonged QT effects over time. By 16 weeks of combination treatment, CFZ, which accumulated slowly without a loading dose, still contributed less than BDQ and DLM. Conclusion This work characterised drug-induced QTcF prolongation over 40 weeks of CFZ and MFX treatment alongside BDQ and DLM in children with RR-TB. Age significantly influenced QTcF at baseline. During combination treatment, CFZ contributed less to QT prolongation than BDQ and DLM. MFX had an immediate post-dose effect and was the primary contributor at its peak concentration.
1. World Health Organization. Operational Handbook on Tuberculosis – Module 5: Management of Tuberculosis in Children and Adolescents.; 2022. https://apps.who.int/iris/bitstream/handle/10665/340256/9789240022614-eng.pdf ?2. Kang J, Wang L, Chen XL, Triggle DJ, Rampe D. Interactions of a Series of Fluoroquinolone Antibacterial Drugs with the Human Cardiac K+ Channel HERG. Mol Pharmacol. 2001;59(1):122-126. doi:10.1124/MOL.59.1.122 ?3. Tadolini M, Lingtsang RD, Tiberi S, et al. Cardiac safety of extensively drug-resistant tuberculosis regimens including bedaquiline, delamanid and clofazimine. European Respiratory Journal. 2016;48(5):1527-1529. doi:10.1183/13993003.01552-2016 ?4. Palmer M, Zou Y, Hesseling AC, et al. Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis. Br J Clin Pharmacol. Published online February 17, 2025. doi:10.1002/BCP.70005 ?5. Hesseling A, Svensson E, Britto P, et al. Pharmacokinetics and safety of bedaquiline in infants, children, and adolescents with rifampicin-resistant TB. The Union World Conference on Lung Health. 2024;(The Union-CDC late-breaker session (epidemiology and programmatic)):LB04-1222-15. Accessed January 13, 2025. https://www.impaactnetwork.org/news/2024/impaact-p1108-primary-results-presented-2024-union-world-conference-lung-health ?6. Sasaki T, Svensson EM, Wang X, et al. Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2022;66(2). doi:10.1128/AAC.01608-21 ?7. Wicha SG, Chen C, Clewe O, Simonsson USH. A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions. Nat Commun. 2017;8(1):2129. doi:10.1038/s41467-017-01929-y ?8. Tanneau L, Karlsson MO, Rosenkranz SL, et al. Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens. Clin Pharmacol Ther. 2022;112(4):873-881. doi:10.1002/cpt.2685
Reference: PAGE 33 (2025) Abstr 11773 [www.page-meeting.org/?abstract=11773]
Poster: Drug/Disease Modelling - Paediatrics