A pharmacometric approach to optimise Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide for children with tuberculosis
Roeland E. Wasmann1∂, Paolo Denti1∂, Annelies van Rie2, Jana Winckler3, Adrie Bekker3, Helena Rabie4, Anneke, C Hesseling3, Louvina E. van der Laan1,3, Carmen Gonzalez-Martinez5, Heather J Zar6, Gerry Davies7,8, Lubbe Wiesner1, Elin M. Svensson9,10, Helen M. McIlleron1,11
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa 2 Family Medicine and Population Health, Faculty of Medicine, University of Antwerp, Antwerp, Belgium 3 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 4 Department of Paediatrics and Child Health and FAMily Centre for Research with Ubuntu (FAMCRU) Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 5 Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi/Liverpool School of Tropical Medicine 6 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 7 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom 8 Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom 9 Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands 10 Department of Pharmacy, Uppsala University, Uppsala, Sweden 11 Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Objectives: While children contribute 11% of all tuberculosis (TB) cases globally, they account disproportionately for TB mortality (14%).1 Reports of low anti-TB drug concentrations in children, compared to adults, prompted the WHO to revise recommended paediatric doses of first-line anti-TB drugs in 2010.2 Pharmacokinetic (PK) studies are required to assess and further optimize the doses of rifampicin (RIF), isoniazid (INH), and pyrazinamide (PZA) to maximize efficacy and safety of all three drugs combined in fixed-dose combinations (FDC). In this analysis, we first present population PK models for each of these drugs to provide insights into exposure achieved with current guidelines. Then we use these models to refine a previously proposed optimisation methodology to (i) improve dosing using the available FDC preparations and (ii) design alternative FDCs to achieve more optimal exposures of RIF, INH, and PZA in children.3
Methods: Children below 12 years of age with and without HIV who were routinely receiving first-line drugs for TB were recruited in a clinical study in Malawi and South Africa. 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 analysed using nonlinear mixed-effects modelling in NONMEM. The final models were used to simulate drug exposures in a representative in-silico paediatric population with a uniform weight distribution (500 patients per kg).4 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 using standard doses were estimated and options for potential new FDCs designed to achieve a median AUC0-24 target range of 38.7-72.9, 11.6-26.3 and 233-429 mg·h/L for RIF, INH and PZA, respectively.5,6 Additionally, new weight bands were estimated simultaneously to optimizes drug exposure throughout children’s development using a previously reported optimization procedure as a basis and building upon it.3
Results: RIF, INH, and PZA plasma concentrations were measured in 841, 843, and 838 samples, respectively, in 180 children (42% female, 14% living with HIV) with median age of 2.0 years [range 0.22-12] and median weight of 11 kg [range 3.2-29]. Clearance and volume parameters were allometrically scaled on 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 positive status did not significantly improve the models. The RIF and INH models included an effect of age on bioavailability to account for lower bioavailability in children <3 years of age.
Simulations showed that median RIF AUC0-24 was below the adult target range in almost all weight groups. Children <3 months of age and <5 kg had higher exposures due to immature clearance. Increasing the number of the currently recommended FDC tablets could result in RIF exposures close to the target, but with unacceptably high INH and PZA exposures. The optimization procedure showed that administering 1, 2, 3, or 4 optimized FDC tablets (RIF/INH/PZA 120/35/130 mg) to children <6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in <3-month-olds with immature metabolism improved exposure for all drugs.
Conclusions: Median RIF plasma exposures in paediatric patients in our study are below the median for adults using standard doses. Using the currently recommended FDCs to optimize RIF exposures results in good exposure to RIF but with high exposures to INH and PZA, compared to typical adults on standard dosing. Therefore, children could benefit from newly designed FDCs containing relatively more RIF and less INH and PZA, to improve drug exposure and treatment outcomes. The targets we used for RIF, INH, and PZA are weighted mean AUC0-24 found in adults at standard doses. Although exposures found in adults are not ideal targets – especially for RIF where higher doses are currently being investigated – at present, they are the only ones available. The optimization procedure we developed is based on previous work and was extended to allow for optimization of drugs with saturable clearance, transit absorption, optimization of a target range and different PD markers (Cmax, Ctrough, time above a concentration).3
 World Health Organization. Global Tuberculosis Report. 2020. Available at: http://library1.nida.ac.th/termpaper6/sd/2554/19755.pdf.
 World Health Organization. Rapid advice: treatment of tuberculosis in children. (2010).
 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).
 Wasmann, R. E., Svensson, E. M., Walker, A. S., Clements, M. N. & Denti, P. Constructing a representative in-silico population for paediatric simulations: Application to HIV-positive African children. Br. J. Clin. Pharmacol. 1–8 (2020) doi:10.1111/bcp.14694.
 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).
 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).