Ruvarashe Joylyne Madzime1, Dr Louvina van der Laan2, Dr Lufina Tsirizani1, Professor Lubbe Wiesner1, Dr Belen Solans3, Professor Rada Savic3, Professor Kelly Dooley4, Dr Shaun Barnabas5, Dr Ingrid Courtney2, Dr Avy Violari6, Professor Paolo Denti1, Professor Anneke Hesseling2
1University of Cape Town, 2Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, 3Department of Bioengineering and Therapeutic Sciences, University of San Francisco Schools of Pharmacy and Medicine, 4Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, 5FAMCRU, Department of Paediatrics and Child Health Faculty of Medicine and Health Sciences, Stellenbosch University, 6Perinatal HIV Research Unit (PHRU), Wits Health Consortium
Introduction: Tuberculosis (TB) infection if untreated can lead to devastating forms of TB disease in young children¹. TB preventive treatment (TPT) is necessary to prevent TB disease. Isoniazid administered once daily for 6 months as TPT has poor completion rates in children in high-burden TB settings. The 3HP regimen (high-dose rifapentine and isoniazid once-weekly for 12 weeks) is highly effective, safer and better tolerated compared to isoniazid monotherapy in adults and children > 2 years of age. However, there is limited data on the pharmacokinetics of isoniazid as part of the 3HP regimen in children < 2 years old, given their exclusion from phase two trials. Young children’s developmental pharmacology significantly impacts drug pharmacokinetics. We characterize the pharmacokinetics of high-dose isoniazid, administered with rifapentine as TPT once weekly over 12 weeks. Methods: Tuberculosis Trials Consortium Study 35 (ClinicalTrials.gov Identifier: NCT03730181) was a phase I/II dose finding and safety study of rifapentine in the context of the 3HP regimen in South African children aged 0–12 years with exposure to drug-susceptible TB (DS-TB), with and without HIV, and without active TB disease. Isoniazid was dosed as a fixed dose tablet with rifapentine once weekly for 12 weeks under directly observed therapy at the trial site. Samples were collected at pre-dose, 1, 2, 4, 8, and 24 h post-dose at week 1, and 1 and 24 h post-dose at week 12. Isoniazid plasma concentrations were assayed using LC-MS/MS at an international accredited laboratory, with a lower limit of quantification of 0.105 ug/mL. We interpreted the data in NONMEM using as a starting point a previous model of isoniazid pharmacokinetics for treatment of DS-TB based on paediatric data (n=387)². We first ran the model with a MAXEVAL=0, to determine the fit of our data based on the previous model population parameter estimates. We then updated the model and re-estimated parameters using FOCE-I. Since NAT2 genotype information was not available, we implemented a mixture model³ with predefined subpopulations – fast/intermediate (74%) vs. slow acetylators (26%) – consistent with South African published data4. We tested an age effect on clearance and bioavailability and an HIV effect on bioavailability . We calculated the area under the curve (AUC) values from the final model to compare with previous reports. Results: Overall, 69 participants were included in the trial, with 53 having available isoniazid concentrations. Of these, 22 (42%) were female and 7 (13%) were living with HIV (ART regimens: abacavir/lamivudine/dolutegravir or tenofovir/lamivudine/dolutegravir). The median (min, max) age was 1.3 (0.07, 12) years, weight 9 (4, 39) kg, and median isoniazid mg/kg dose was 16.7 (10.7, 24.2) mg/kg. Isoniazid pharmacokinetics was best described by a 2-compartment disposition model with first order transit absorption . Disposition parameters were allometrically scaled using total body weight. The typical clearance values were 6.85 L/h for fast/intermediate acetylators and 2.8 L/h for slow acetylators. An age effect on clearance was identified (p < 0.05), with 50% maturation being reached at approximately 1 month of age and full maturation at approximately 18 months of age. The median isoniazid (IQR) AUC was 31.3 (21.4, 55.2) mg·h/L. The treatment was safe and well tolerated, with no reported grade 3 adverse events. Conclusions: Our model adequately described the pharmacokinetics of once-weekly high-dose isoniazid in young children with and without HIV. Our parameter estimates are in line with values reported in literature² 4 5. The model was more parsimonious having two fixed populations in the mixture model, instead of three, and this made the parameters more stable. Contrary to previously published models, we found no age effect on bioavailability, which may be due to different formulations used in that study². We found no HIV (p> 0.05) effect on bioavailability, consistent with previous findings². The observed AUCs were higher than those reported in the large phase 3 multisite SHINE efficacy trial- which included children from South Africa, Zambia, Uganda and India, where children received daily isoniazid at 10 – 15 mg/kg for treatment of TB disease over 16-24 months, resulting in a median (IQR) AUC of 16.7 (9.2, 25.9) mg·h/L6. Compared to first-line TB treatment, the higher isoniazid doses used in 3HP resulted in proportionally higher AUCs, but the study had good safety outcomes and tolerability .
1. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8(4):392-402. 2. Galileya LT, Wasmann RE, Chabala C, et al. Evaluating pediatric tuberculosis dosing guidelines: a model-based individual data pooled analysis. PLoS Med. 2023;20(11):e1004303. doi:10.1371/journal.pmed.1004303 3. Ette EI, Williams Paul J. Pharmacometrics: The Science of Quantitative Pharmacology. First. (Ette EI, Williams Paul J, eds.). John Wiley & Sons, Inc; 2007. 4. Denti P, Wasmann RE, Van Rie A, et al. Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study. Clinical Infectious Diseases. 2022;75(1). doi:10.1093/cid/ciab908 5. Zvada SP, Denti P, Donald PR, et al. Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses. Journal of Antimicrobial Chemotherapy. 2014;69(5). doi:10.1093/jac/dkt524 6. Chabala C, Turkova A, Thomason MJ, et al. Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial. Trials. 2018;19(1):237. doi:10.1186/s13063-018-2608-5
Reference: PAGE 33 (2025) Abstr 11559 [www.page-meeting.org/?abstract=11559]
Poster: Drug/Disease Modelling - Paediatrics