Challenges of Monitoring Blood Levels of Bedaquiline in Drug-Resistant Tuberculosis: A Narrative Review
DOI:
https://doi.org/10.59188/eduvest.v5i3.50267Keywords:
Bedaquiline, TDM, Pharmacokinetics, TB, MDR-TBAbstract
Bedaquiline, a second-line drug for drug-resistant tuberculosis (MDR-TB), is one of the latest generation drugs in the treatment of tuberculosis (TB). However, the challenge in determining the optimal dose and individual pharmacokinetic variability requires the implementation of Therapeutic Drug Monitoring (TDM). This article aims to evaluate the challenges of TDM bedaquiline through a narrative review of the current literature. Relevant articles were identified through computerized searches on PubMed and Google Scholar using a combination of keywords related to bedaquiline, pharmacokinetics, and TDM. Limited clinical data indicate a lack of standard exposure targets and reliable efficacy thresholds. Pharmacokinetic variability is influenced by factors such as age, weight, gender, genetics, comorbidities, and serum albumin. Technical challenges include the need for precise analytical methods and the accessibility of technology in clinical practice. The use of TDM for bedaquiline offers the potential to improve the efficacy of MDR-TB treatment, but more research is needed to address pharmacokinetic variability and develop standardized guidelines.
References
Alffenaar, J. W. C., Bolhuis, M., van hateren, K., Sturkenboom, M., Akkerman, O., De Lange, W., Greijdanus, B., Van der Werf, T., & Touw, D. (2015). Determination of bedaquiline in human serum using liquid chromatography-tandem mass spectrometry. Antimicrobial Agents and Chemotherapy, 59(9), 5675–5680. https://doi.org/10.1128/AAC.00276-15
Alghamdi, W. A., Al-Shaer, M. H., Kipiani, M., Barbakadze, K., Mikiashvili, L., Kempker, R. R., & Peloquin, C. A. (2021). Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis. Journal of Antimicrobial Chemotherapy, 76(4), 1019–1024. https://doi.org/10.1093/jac/dkaa550
Bensalem, A., & Ternant, D. (2020). Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications. Clinical Pharmacokinetics, 59(7), 857–874. https://doi.org/10.1007/s40262-020-00874-2
Bhatnagar, A. K., Hemanthkumar, A. K., Muthu Vijayalakshmi, M., Vohra, V., Padmapriyadarsini, C., Ramesh, P. M., Taneja, G., Chavan, V. N., Jeyadeepa, B., Bhui, N. K., & Solanki, R. (2024). Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis. Therapeutic Drug Monitoring, 46(3), 363–369. https://doi.org/10.1097/FTD.0000000000001164
Bolhuis, M. S., Akkerman, O. W., Sturkenboom, M. G. G., de Lange, W. C. M., van der Werf, T. S., & Alffenaar, J. W. C. (2016). Individualized treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring. International Journal of Mycobacteriology, 5, S44–S45. https://doi.org/10.1016/j.ijmyco.2016.07.003
Burns, M. L., Baftiu, A., Opdal, M. S., Johannessen, S. I., & Landmark, C. J. (2016). Therapeutic drug monitoring of clobazam and its metabolite-impact of age and comedication on pharmacokinetic variability. Therapeutic Drug Monitoring, 38(3), 350–357. https://doi.org/10.1097/FTD.0000000000000272
Cardoso, E., Csajka, C., Schneider, M. P., & Widmer, N. (2018). Effect of Adherence on Pharmacokinetic/Pharmacodynamic Relationships of Oral Targeted Anticancer Drugs. Clinical Pharmacokinetics, 57(1), 1–6. https://doi.org/10.1007/s40262-017-0571-z
Diacon, A. H., Dawson, R., Von Groote-Bidlingmaier, F., Symons, G., Venter, A., Donald, P. R., Conradie, A., Erondu, N., Ginsberg, A. M., Egizi, E., Winter, H., Becker, P., & Mendel, C. M. (2013). Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. Antimicrobial Agents and Chemotherapy, 57(5), 2199–2203. https://doi.org/10.1128/AAC.02243-12
Eliasson, E., Lindh, J. D., Malmström, R. E., Beck, O., & Dahl, M. L. (2013). Therapeutic drug monitoring for tomorrow. European Journal of Clinical Pharmacology, 69(SUPPL. 1), 25–32. https://doi.org/10.1007/s00228-013-1504-x
Encinas, M. V., Lissi, E., & Vergara, C. (2013). Association of valdecoxib, a nonsteroidal anti-inflammatory drug, with human serum albumin. Photochemistry and Photobiology, 89(6), 1399–1405. https://doi.org/10.1111/php.12158
Esposito, S., Bianchini, S., & Blasi, F. (2015). Bedaquiline and delamanid in tuberculosis. Expert Opinion on Pharmacotherapy, 16(15), 2319–2330. https://doi.org/10.1517/14656566.2015.1080240
Eusuf, D. V., & Thomas, E. (2022). Pharmacokinetic variation. Anaesthesia and Intensive Care Medicine, 23(1), 50–53. https://doi.org/10.1016/j.mpaic.2021.10.014
Fang, Z., Zhang, H., Guo, J., & Guo, J. (2024). Overview of therapeutic drug monitoring and clinical practice. Talanta, 266(P1), 124996. https://doi.org/10.1016/j.talanta.2023.124996
Flores-Pérez, C., Flores-Pérez, J., Moreno-Rocha, L. A., Chávez-Pacheco, J. L., Noguez-Méndez, N. A., Ramírez-Mendiola, B., Sánchez-Maza, Y., & Sarmiento-Argüello, L. (2023). Influence of Age and Sex on the Pharmacokinetics of Midazolam and the Depth of Sedation in Pediatric Patients Undergoing Minor Surgeries. Pharmaceutics, 15(2). https://doi.org/10.3390/pharmaceutics15020440
Gray, W. A., Waldorf, B., Rao, M. G., Stiles, B. L., Griffiss, J. M. L., Salata, R. A., & Blumer, J. L. (2019). Development and validation of an LC-MS/MS method for the simultaneous determination of bedaquiline and rifabutin in human plasma. Journal of Pharmaceutical and Biomedical Analysis, 176, 112775. https://doi.org/10.1016/j.jpba.2019.07.023
Hughes, J. A., Solans, B. D. S. P., Draper, H. R., Schaaf, H. S., Winckler, J. L., Van Der Laan, L., Radtke, K. K., Fourie, B., Wiesner, L., Hesseling, A. C., Savic, R. M., & Garcia-Prats, A. J. (2022). Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents with Rifampicin-Resistant Tuberculosis. Clinical Infectious Diseases, 75(10), 1772–1780. https://doi.org/10.1093/cid/ciac252
Krogstad, V., Peric, A., Robertsen, I., Kringen, M. K., Vistnes, M., Hjelmesæth, J., Sandbu, R., Johnson, L. K., Angeles, P. C., Jansson-Löfmark, R., Karlsson, C., Andersson, S., Åsberg, A., Andersson, T. B., & Christensen, H. (2021). Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes. Journal of Pharmaceutical Sciences, 110(1), 432–437. https://doi.org/10.1016/j.xphs.2020.10.027
Larsen, M. T., Kuhlmann, M., Hvam, M. L., & Howard, K. A. (2016). Albumin-based drug delivery: harnessing nature to cure disease. Molecular and Cellular Therapies, 4(1), 1–12. https://doi.org/10.1186/s40591-016-0048-8
Li, J., Yang, G., Cai, Q., Wang, Y., Xu, Y., Zhang, R., Lang, Y., & Cai, X. (2021). Safety, efficacy, and serum concentration monitoring of bedaquiline in Chinese patients with multidrug-resistant tuberculosis. International Journal of Infectious Diseases, 110, 179–186. https://doi.org/10.1016/j.ijid.2021.07.038
Maranchick, N. F., & Peloquin, C. A. (2024). Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 36(April), 100444. https://doi.org/10.1016/j.jctube.2024.100444
Mauvais-Jarvis, F., Berthold, H. K., Campesi, I., Carrero, J. J., Dakal, S., Franconi, F., Gouni-Berthold, I., Heiman, M. L., Kautzky-Willer, A., Klein, S. L., Murphy, A., Regitz-Zagrosek, V., Reue, K., & Rubin, J. B. (2021). Sex-and gender-based pharmacological response to drugss. Pharmacological Reviews, 73(2), 730–762. https://doi.org/10.1124/pharmrev.120.000206
McLeay, S. C., Vis, P., Van Heeswijk, R. P. G., & Green, B. (2014). Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug. Antimicrobial Agents and Chemotherapy, 58(9), 5315–5324. https://doi.org/10.1128/AAC.01418-13
Pai, M., Behr, M. A., Dowdy, D., Dheda, K., Divangahi, M., Boehme, C. C., Ginsberg, A., Swaminathan, S., Spigelman, M., Getahun, H., Menzies, D., & Raviglione, M. (2016). Tuberculosis. Nature Reviews Disease Primers, 2. https://doi.org/10.1038/nrdp.2016.76
Peloquin, C. (2017). The Role of Therapeutic Drug Monitoring in Mycobacterial Infections. Microbiology Spectrum, 5(1). https://doi.org/10.1128/microbiolspec.TNMI7-0029-2016
Perrineau, S., Lachâtre, M., Lê, M. P., Rioux, C., Loubet, P., Fréchet-Jachym, M., Cervantes Gonzales, M., Grall, N., Bouvet, E., Veziris, N., Yazdanpanah, Y., & Peytavin, G. (2019). Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis. International Journal of Tuberculosis and Lung Disease, 23(1), 99–104. https://doi.org/10.5588/ijtld.18.0042
Sarathy, J. P., Gruber, G., & Dick, T. (2019). Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline. Antibiotics, 8(4). https://doi.org/10.3390/antibiotics8040261
Seung, K. J., Keshavjee, S., & Rich, M. L. (2015). Drug-Resistant Tuberculosis.
Shao, G., Bao, Z., Davies Forsman, L., Paues, J., Werngren, J., Niward, K., Schön, T., Bruchfeld, J., Alffenaar, J. W., & Hu, Y. (2023). Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients. Frontiers in Pharmacology, 14(March), 1–12. https://doi.org/10.3389/fphar.2023.1022090
Svensson, E. M., Dosne, A. G., & Karlsson, M. O. (2016). Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients with Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin. CPT: Pharmacometrics and Systems Pharmacology, 5(12), 682–691. https://doi.org/10.1002/psp4.12147
Umehara, K., Yama, K., Goto, K., Hoshi, T., Hatakeyama, T., Isaji, M., Takada, S., Yamagishi, K., Mino, K., & Sato, H. (2023). Serum Albumin Affects the Time-to-treatment Failure of Alectinib: A Multicenter Retrospective Study. In Vivo, 37(5), 2260–2267. https://doi.org/10.21873/invivo.13328
van Heeswijk, R. P. G., Dannemann, B., & Hoetelmans, R. M. W. (2014). Bedaquiline: A review of human pharmacokinetics and drug-drug interactions. Journal of Antimicrobial Chemotherapy, 69(9), 2310–2318. https://doi.org/10.1093/jac/dku171
Wilby, K. J., & Hussain, F. N. (2020). A Review of Clinical Pharmacokinetic and Pharmacodynamic Relationships and Clinical Implications for Drugs Used to Treat Multi-drug Resistant Tuberculosis. European Journal of Drug Metabolism and Pharmacokinetics, 45(3), 305–313. https://doi.org/10.1007/s13318-019-00604-5
World Health Organization (WHO). (2013). The use of bedaquiline in the treatment of.
World Organization for Animal Health. (2023). Report 20-23. In January: Vol. t/malaria/ (Issue March).
Zou, J., Chen, S., Rao, W., Fu, L., Zhang, J., Liao, Y., Zhang, Y., Lv, N., Deng, G., Yang, S., Lin, L., Li, L., Liu, S., & Qu, J. (2022). Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China. Antimicrobial Agents and Chemotherapy, 66(10). https://doi.org/10.1128/aac.00811-2
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