Roeland E. Wasmann1, Paolo Denti1, Elin M. Svensson2,3, Carmen Gonzales4, Jana Winckler5, Adrie Bekker5, Helena Rabie6, Anneke, C Hesseling5, Louvina van der Laan1,5, Heather J Zar7, Lubbe Wiesner1, Annelies van Rie5, Gerry Davies8,9, Helen McIlleron1
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; (3) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (4) Malawi-Liverpool-Wellcome Trust Clinical Research Unit; (5) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; (6) Department of Paediatrics and Child Health and Children's Infectious Diseases Clinical Research Unit, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa; (7) Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, and SA-MRC Unit on Child & Adolescent Health, University of Cape Town, South Africa; (8) Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; (9) Institute of Global Health, University of Liverpool, Liverpool, UK;
Objectives: While children make up 11% of all TB cases, they contribute disproportionately to TB mortality (14%).1 Reports of low tuberculosis (TB) drug concentrations in children, when compared to adults, prompted the WHO to revise the recommended pediatric doses of tuberculosis drugs in 2010.2 Pharmacokinetic studies are required to assess and further optimize the doses in order to maximize efficacy and safety of all three drugs combined in fixed-dose combinations (FDCs). We present population pharmacokinetic (PK) models to provide insights into drug exposure under current guidelines, provide possibilities of dose optimization using the available FDC preparations and optimize the FDC formulations to achieve optimal exposures of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA).
Methods: Children below 12 years of age receiving first-line drugs for TB disease in Malawi and South Africa were included. Intensive PK sampling in the second month of therapy (at steady state) was performed to quantify RIF, INH and PZA concentrations. PK parameters and relevant covariates were analyzed using nonlinear mixed effects modeling. The final models were used to simulate drug exposures in a representative in-silico pediatric population with a uniform age-distribution (400 patients per age-month).3 Steady-state AUC0-24 after dosing according to WHO recommendations with existing FDCs (RIF/INH/PZA 75/50/150 mg, with 1, 2, 3 and 4 tablets for weight bands 4-7.9, 8-11.9, 12-15.9 and 16-24.9 kg, respectively) was estimated. Optimized doses achieving AUC0-24 comparable to typical adult exposures on standard doses, were estimated and new FDCs designed to achieve target median AUC0-24 of 38.7, 15.6 and 353 mg*h/L for RIF, INH and PZA, respectively, in a second in-silico pediatric population with a uniform weight-distribution (500 patients per kg).3–5
Results: RIF, INH and PZA plasma concentrations were measured in 849 samples from 179 children (42% female, 9% HIV-infected) with median age of 1.9 years [range 0.22-12] and median weight of 10.7 kg [range 3.20-28.8]. Clearance and volume parameters were allometrically scaled on bodyweight/fat-free mass, and all models included a maturation function to describe the change in clearance with post-menstrual age. After accounting for these effects, HIV infection status did not significantly improve the models. The RIF model included an effect of age on bioavailability to account for lower bioavailability in children younger than 3 years old.
Simulations showed that for all children >3 months-old, median RIF AUC0-24 was lower than the median exposure reported in adults.4,5 Children under 3 months-old and weighing
Conclusions: Median RIF plasma exposures in pediatric patients in our study are below the median for adults. Using the currently recommended FDCs to optimize RIF exposures results in a good exposure to RIF but with high exposures to INH and PZA, compared to typical adults on standard dosing. Therefore, pediatric patients could benefit from newly designed FDCs containing relatively more RIF and less INH and PZA, to improve treatment and outcomes. The targets for INH and PZA are weighted mean AUC0-24 found in adults at standard doses, although typical AUC0-24 in adults is not ideal these targets are currently the only available target. Children under 3 months-old and weighing
References:
[1] World Health Organization. Global Tuberculosis Report. (2019).
[2] World Health Organization. Rapid advice: treatment of tuberculosis in children. (2010).
[3] Svensson, E. M. et al. Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy. Clin. Pharmacokinet. 57, 591–599 (2018).
[4] Stott, K. E. et al. Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis. J. Antimicrob. Chemother. 73, 2305–2313 (2018).
[5] Daskapan, A. et al. A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs. Clin. Pharmacokinet. 58, 747–766 (2019).
Reference: PAGE () Abstr 9503 [www.page-meeting.org/?abstract=9503]
Poster: Oral: Drug/Disease Modelling