Identification of Urine Biomarkers Predictive of Prolonged QTc Interval in Multidrug-resistant Tuberculosis Patients Treated with Bedaquiline

Overview

Journal Front Pharmacol

Date 2024 Jun 14

PMID 38873419

Authors

Jiajia Yu

Weicong Ren

Jinfeng Yuan

Rongmei Liu

Liping Ma

Shenjie Tang

Yu Pang

Affiliations

Soon will be listed here.

Abstract

The most frequent adverse event associated with bedaquiline (BDQ) is the QTc interval prolongation; however, there was no biomarkers that could be used to predict the occurrence of QTc prolongation in BDQ-treated patients. In this study, we employed the ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) to generate metabolic profiling for the discovery of potential predictive urine biomarkers of QTc prolongation in these patients. Untargeted metabolomic technique was used to concentrate the differential metabolic pathway, and targeted metabolomic technique was subsequently performed to identify predictive biomarkers for QTc prolongation. A total of 45 rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) patients were enrolled in our study, including 15 RR/MDR-TB patients with QTc interval prolongation (QIP) and 30 RR/MDR-TB patients with QTc interval un-prolongations (QIU). Untargeted technique revealed that the lipid metabolism was the most differential metabolic pathway between two groups. Further targeted technique identified four differential metabolites, including betaine, LPE (18:2), LPE (20:3), and LPE (20:4). The combined analysis of metabolisms revealed that the combined use of LPE (20:3) and LPE (20:4) had the best performance for predicting the occurrence of QTc prolongation in TB patients, yielding a sensitivity of 87.4% and a specificity of 78.5%. In addition, with the progression of BDQ treatment, the LPEs exhibited persistent difference in the BDQ-treated TB patients experiencing QTc interval prolongation. In conclusion, our data demonstrate that the combined use of LPE (20:3) and LPE (20:4) yields promising performance for predicting the occurrence of QTc interval prolongation in BDQ-treated patients.

References

Lee J, Park S, Im D . Calcium Signaling of Lysophosphatidylethanolamine through LPA in Human SH-SY5Y Neuroblastoma Cells. Biomol Ther (Seoul). 2016; 25(2):194-201. PMC: 5340545. DOI: 10.4062/biomolther.2016.046. View

Meikle P, Summers S . Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol. 2016; 13(2):79-91. DOI: 10.1038/nrendo.2016.169. View

Nyangwa B, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z . Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. Lancet Respir Med. 2023; 12(2):117-128. DOI: 10.1016/S2213-2600(23)00389-2. View

Harpole M, Davis J, Espina V . Current state of the art for enhancing urine biomarker discovery. Expert Rev Proteomics. 2016; 13(6):609-26. PMC: 4978532. DOI: 10.1080/14789450.2016.1190651. View

Duan L, Gan H, Arm J, Remold H . Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. J Immunol. 2001; 166(12):7469-76. DOI: 10.4049/jimmunol.166.12.7469. View

Kowalewski N, Forster C . Collection, Processing, and Storage Consideration for Urinary Biomarker Research. J Vis Exp. 2021; (176). DOI: 10.3791/62453. View

Diacon A, Pym A, Grobusch M, de los Rios J, Gotuzzo E, Vasilyeva I . Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014; 371(8):723-32. DOI: 10.1056/NEJMoa1313865. View

Dooley K, Rosenkranz S, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F . QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021; 21(7):975-983. PMC: 8312310. DOI: 10.1016/S1473-3099(20)30770-2. View

Bi X, Liu W, Ding X, Liang S, Zheng Y, Zhu X . Proteomic and metabolomic profiling of urine uncovers immune responses in patients with COVID-19. Cell Rep. 2022; 38(3):110271. PMC: 8712267. DOI: 10.1016/j.celrep.2021.110271. View

10.

Tan S, Ramesh T, Toh X, Nguyen L . Emerging roles of lysophospholipids in health and disease. Prog Lipid Res. 2020; 80:101068. DOI: 10.1016/j.plipres.2020.101068. View

11.

Hurley B, McCormick B . Multiple roles of phospholipase A2 during lung infection and inflammation. Infect Immun. 2008; 76(6):2259-72. PMC: 2423084. DOI: 10.1128/IAI.00059-08. View

12.

Dookie N, Ngema S, Perumal R, Naicker N, Padayatchi N, Naidoo K . The Changing Paradigm of Drug-Resistant Tuberculosis Treatment: Successes, Pitfalls, and Future Perspectives. Clin Microbiol Rev. 2022; 35(4):e0018019. PMC: 9769521. DOI: 10.1128/cmr.00180-19. View

13.

Aragon I, Herrera-Imbroda B, Queipo-Ortuno M, Castillo E, Del Moral J, Gomez-Millan J . The Urinary Tract Microbiome in Health and Disease. Eur Urol Focus. 2017; 4(1):128-138. DOI: 10.1016/j.euf.2016.11.001. View

14.

Duflot T, Tu L, Leuillier M, Messaoudi H, Groussard D, Feugray G . Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?. Metabolites. 2021; 11(11). PMC: 8621392. DOI: 10.3390/metabo11110784. View

15.

Gao M, Gao J, Xie L, Wu G, Chen W, Chen Y . Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect. 2020; 27(4):597-602. DOI: 10.1016/j.cmi.2020.06.004. View

16.

Pontali E, Sotgiu G, Tiberi S, DAmbrosio L, Centis R, Migliori G . Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. Eur Respir J. 2017; 50(5). DOI: 10.1183/13993003.01462-2017. View

17.

Arking D, Pulit S, Crotti L, van der Harst P, Munroe P, Koopmann T . Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet. 2014; 46(8):826-36. PMC: 4124521. DOI: 10.1038/ng.3014. View

18.

Chorell E, Olsson T, Jansson J, Wennberg P . Lysophospholipids as Predictive Markers of ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI). Metabolites. 2021; 11(1). PMC: 7823877. DOI: 10.3390/metabo11010025. View

19.

Piotrovsky V . Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation. AAPS J. 2005; 7(3):E609-24. PMC: 2751265. DOI: 10.1208/aapsj070363. View

20.

Lyu X, Lin T, Gao J, Jia H, Zhu C, Li Z . Effects of Bedaquiline on Antimicrobial Activity and Cytokine Secretion of Macrophages Infected with Multidrug-Resistant Strains. Can J Infect Dis Med Microbiol. 2022; 2022:2703635. PMC: 9017561. DOI: 10.1155/2022/2703635. View