Investigating Alternative Daily Dose Regimens for Bedaquiline in Treatment of Multidrug-Resistant Tuberculosis using an Interactive Shiny Application
Frances Okibedi, Yuanxi Zou and Elin M Svensson
1. Department of Pharmacy, Uppsala University, Sweden 2. Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, The Netherlands
Objectives: Tuberculosis (TB) remains a major global health concern, especially multidrug-resistant (MDR) TB [1]. Bedaquiline (BDQ), is an effective drug for MDR-TB treatment [2]. The approved BDQ dose regimen for adults includes a loading dose of 400 mg daily (QD) for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks, generally with three to four drugs co-administered QD according to the World Health Organization (WHO) guidelines [1]. The divergent dosing schedule of BDQ could increase the risk of poor adherence, which may affect treatment outcomes, and it obstructs the formulation of fixed-dose combination tablets including BDQ. Therefore, a QD dose regimen of BDQ is desired to simplify dosing, maintain therapeutic levels, and possibly facilitate a fixed-dose combination with other anti-TB drugs in the future. A simulation study from TB Alliance showed that a BDQ QD regimen of 200 mg for 8 weeks followed by 100 mg for 16 weeks has a comparable exposure to the approved regimen in the later part of treatment but lower in the beginning [3]. This TB Alliance regimen has also been tested in the recent ZENIX trials [4].
Our project aimed to investigate an alternative QD BDQ regimen with the same loading phase as the approved regimen, and to implement a shiny tool for interactive simulation of typical and population concentration profiles under different dosing regimens.
Methods: An established population pharmacokinetic (PK) model of BDQ and its metabolite M2, developed on data from two phase IIb studies was used [5]. The model includes two transit compartments for BDQ absorption as well as three and one disposition compartments for BDQ and M2, respectively [5]. The NONMEM code of the model was implemented in R using the “mrgsolve” package [6]. A shiny app was also implemented to enable the exploration of different BDQ dose regimens.
Simulations were conducted for a 32 years-old patient with a baseline body weight of 53 kg, baseline albumin concentrations of 3.50 g/dl and black or non-black race. Three BDQ regimens of 24 weeks were investigated: the approved regimen, the TB alliance regimen and a new proposed regimen(400 mg QD for 2 weeks followed by 100 mg QD for 22 weeks).
To compare regimens, simulated PK profiles, trough concentrations, mean weekly concentration (Cavg_weekly), cumulative area under the concentration-time profile (CumAUC), as well as PK profile after dosing at 2, 8 and 24 weeks were plotted using the ggplot2 package.
Results: The output of the mrgsolve simulation showed comparable PK metrics with the NONMEM simulation which confirmed that the mrgsolve model translation was done correctly. The shiny app was implemented to allow users to customize dosing (including or not including loading phase of different durations), covariates, drug interactions, and simulation details for single regimen and regimen comparison panels. It will be published as open source.
For the approved and new proposed regimen, the maintenance phase which lasted from week 2 until week 22, showed an initial decrease in exposure followed by a comparable increase in exposure. The cumAUC plots showed that the total BDQ exposure with the TB Alliance regimen intersected with the approved regimen (1300 mg*hr/L) at week 7 and the newly proposed regimen (1425 mg*hr/L) at week 8. The TB Alliance treatment showed a typical weekly average BDQ concentration of 1.6 mg/L at week 8, which was lower than the other two regimens' concentration of 1.8 mg/L.
For the M2 concentrations, the TB Alliance treatment had a concentration of 0.45mg/L at 8 weeks, higher than the approved (0.29mg/L) and newly proposed (0.34mg/L) regimens. At 24 weeks, the TB Alliance treatment's concentration of 0.38 mg/L was also higher than the approved (0.32 mg/L) and new proposed (0.36 mg/L) regimens in the non-black race and showed the same trend in the black race.
Conclusions: The developed shiny app will enable easy exploration of alternative BDQ regimens, the impact of drug-drug interactions and covariates. The new proposed QD dose had similar BDQ and M2 concentrations as the approved dose regimen throughout the treatment period at the maintenance phase and could be tested in clinical trials.
References:
[1] World Health Organization, Global Tuberculosis Report 2021. Geneva: World Health Organization; 2021.
[2] Diacon A.H, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21;371(8):723-732.
[3] D. H. Salinger, J. R. Nedelman, C. Mendel, M. Spigelman, and D. J. Hermann, ‘Daily dosing for bedaquiline in patients with tuberculosis’, Antimicrob Agents Chemother, vol. 63, no. 11, pp. 463–482, 2019, doi: 10.1128/AAC.00463-19/
[4] F. Conradie, T.R. Bagdasaryan, S. Borisov, et al, 2022. Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1; 387(9): 810-823; doi: 10.1056/NEJMoa2119430
[5] Svensson EM, Dosne A-G and Karlsson MO. 2016. Population Pharmacokinetics of bedaquiline and Metabolite M2 in Patients with Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin. CPT Pharmacometrics System. Pharmacology. (2016) 5, 682–691; doi:10.1002/psp4.12147
[6] Metrum Research Institute. ‘Mrgsolve User Guide’. https://mrgsolve.org/user_guide
