Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis
Abstract
:1. Introduction
2. Results and Discussions
2.1. Participants Profile
2.2. Pharmacokinetic Parameters of Linezolid
2.3. Relationship between LZD Exposure and Toxicity
2.3.1. Anemia and Plasma Levels of LZD
2.3.2. Peripheral Neuropathy (PN)
2.3.3. Blurring of Vision and Optic Neuritis
2.4. Sparse PK
2.5. Discussions
3. Materials and Methods
3.1. Study Design and Setting
3.2. Intense and Sparse Pharmacokinetics
3.3. Drug Estimation and Analysis
3.4. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Disclaimer
References
- World Health Organization. Global Tuberculosis Report 2022; World Health Organization: Geneva, Switzerland, 2022. Available online: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022 (accessed on 19 January 2023).
- Pontali, E.; Raviglione, M.C.; Migliori, G.B. Regimens to treat multidrug-resistant tuberculosis: Past, present and future perspectives. Eur. Resp. Rev. 2019, 28, 190035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Singh, B.; Cocker, D.; Ryan, H.; Sloan, D.J. Linezolid for drug-resistant pulmonary tuberculosis. Cochrane Database Syst. Rev. 2019, 3, CD012836. [Google Scholar] [PubMed]
- Singla, R.; Caminero, J.A.; Jaiswal, A.; Singla, N.; Gupta, S.; Bali, R.K.; Behera, D. Linezolid: An effective, safe and cheap drug for patients failing multidrug-resistant tuberculosis treatment in India. Eur. Respir. J. 2012, 39, 956–996. [Google Scholar] [CrossRef] [PubMed]
- World Health Organization. WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment; World Health Organization: Geneva, Switzerland, 2019.
- Lan, Z.; Ahmad, N.; Baghaei, P.; Barkane, L.; Benedetti, A.; Brode, S.K.; Brust, J.C.M.; Campbell, J.R.; Chang, V.W.L.; Falzon, D.; et al. Drug-associated adverse events in the treatment of multi drug-resistant tuberculosis: An individual patient data meta-analysis. Lancet Respir. Med. 2020, 8, 383–394. [Google Scholar] [CrossRef] [PubMed]
- Conradie, F.; Diacon, A.H.; Ngubane, N.; Howell, P.; Everitt, D.; Crook, A.M.; Mendel, C.M.; Egizi, E.; Moreira, J.; Timm, J.; et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N. Engl. J. Med. 2020, 382, 893–902. [Google Scholar] [CrossRef] [PubMed]
- Tornheim, J.A.; Intini, E.; Gupta, A.; Udwadia, Z.F. Clinical features associated with linezolid resistance among multidrug resistant tuberculosis patients at a tertiary care hospital in Mumbai, India. J. Clin. Tuberc. Mycobact. Dis. 2020, 20, 100175. [Google Scholar]
- Wasserman, S.; Meintjes, G.; Maartens, G. Linezolid in the treatment of drug-resistant tuberculosis: The challenge of its narrow therapeutic index. Expert Rev. Anti Infect. Ther. 2016, 14, 901–915. [Google Scholar] [CrossRef] [PubMed]
- Song, T.; Lee, M.; Jeon, H.S.; Park, Y.; Dodd, L.E.; Dartois, V.; Follman, D.; Wang, J.; Cai, Y.; Goldfeder, L.C.; et al. Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis. eBioMedicine 2015, 2, 1627–1633. [Google Scholar]
- Srivastava, S.; Pasipanodya, J.G.; Meek, C.; Leff, R.; Gumbo, T. Multidrug-Resistant Tuberculosis not due to Noncompliance but to Between-Patient Pharmacokinetic Variability. J. Infect. Dis. 2011, 204, 1951–1959. [Google Scholar] [CrossRef]
- Lifan, Z.; Sainan, B.; Feng, S.; Siyan, Z.; Xiaoquing, L. Linezolid for the treatment of extensively drug-resistant tuberculosis: A systematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 2019, 23, 1293–1307. [Google Scholar] [CrossRef]
- Agyemann, A.A.; Ofori-Aseno, R. Efficacy and safety profile of linezolid in the treatment of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis: A systematic review and meta-analysis. Ann. Clin. Microbiol. Antimicrob. 2016, 15, 41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Padmapriyadarsini, C.; Vohra, V.; Bhatnagar, A.; Solanki, R.; Sridhar, R.; Anande, L.; Muthuvijaylakshmi, M.; Bhatia, M.; Jeyadeepa, B.; Taneja, G.; et al. Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis. Clin. Infect. Dis. 2022, 76, e938–e946. [Google Scholar] [CrossRef] [PubMed]
- Wasserman, S.; Brust, J.C.M.; Abdelwahab, M.T.; Little, F.; Denti, P.; Wiesner, L.; Gandhi, N.R.; Meintjes, G.; Maartens, G. Linezolid toxicity in patients with drug-resistant tuberculosis: A prospective cohort study. J. Antimicrob. Chemother. 2022, 77, 1146–1154. [Google Scholar] [CrossRef] [PubMed]
- Morata, L.; De la Calle, C.; Gómez-Cerquera, J.M.; Manzanedo, L.; Casals, G.; Brunet, M.; Cobos-Trigueros, N.; Martínez, J.A.; Mensa, J.; Soriano, A. Risk factors associated with high linezolid trough plasma concentrations. Expert Opin. Pharmacother. 2016, 17, 1183–1187. [Google Scholar] [CrossRef]
- Bigelow, K.M.; Deitchman, A.N.; Li, S.Y.; Barnes-Boyle, K.; Tyagi, S.; Soni, H.; Dooley, K.E.; Savic, R.M.; Nuermberger, E. Pharmacodynamic correlates of linezolid activity and toxicity in murine models of tuberculosis. J. Infect. Dis. 2021, 223, 1855–1864. [Google Scholar] [CrossRef] [Green Version]
- Huo, B.N.; Wu, Y.E.; Shu, L.; Zhang, R.Q.; Xiao, J.W.; Li, Q.B.; Zhao, W.; Jia, Y.T.; Song, L. Relationship Between Linezolid Exposure and the Typical Clinical Laboratory Safety and Bacterial Clearance in Chinese Pediatric Patients. Front. Pharmacol. 2022, 13, 926711. [Google Scholar] [CrossRef]
- Luque, S.; Hope, W.; Sorli, L.; Muñoz-Bermudez, R.; Campillo, N.; Barceló-Vidal, J.; Álvarez-Lerma, F.; Horcajada, J.P.; Masclans-Enviz, J.R.; Neely, M.; et al. Dosage Individualization of Linezolid: Precision Dosing of Linezolid to Optimize Efficacy and Minimize Toxicity. Antimicrob. Agents Chemother. 2021, 65, e02490-20. [Google Scholar] [CrossRef]
- Wu, F.; Zhang, X.S.; Dai, Y.; Zhou, Z.Y.; Zhang, C.H.; Han, L.; Xu, F.M.; Wang, Y.X.; Shi, D.W.; Lin, G.Y.; et al. Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients. Front. Pharmacol. 2022, 13, 844567. [Google Scholar] [CrossRef]
- Bandín-Vilar, E.; García-Quintanilla, L.; Castro-Balado, A.; Zarra-Ferro, I.; González-Barcia, M.; Campos-Toimil, M.; Mangas-Sanjuan, V.; Mondelo-García, C.; Fernández-Ferreiro, A. A Review of Population Pharmacokinetic Analyses of Linezolid. Clin. Pharmacokinet. 2022, 61, 789–817. [Google Scholar] [CrossRef]
- Vijayakumar, A.; Sudha, V.; Alffenaar, J.W.; Jeyakumar, S.M.; Hemanth Kumar, A.K. A simple HPLC-UV method for therapeutic drug monitoring of Linezolid in human plasma in low-resourced settings. J. Appl. Bioanal. 2021, 7, e21008. [Google Scholar]
- Galar, A.; Valerio, M.; Muñoz, P.; Alcalá, L.; García-González, X.; Burillo, A.; Sanjurjo, M.; Grau, S.; Bouza, E. Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact. Antimicrob. Agents Chemother. 2017, 61, e00687-17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DAIDS. Table for Grading the Severity of Adult and Pediatric Adverse Events; Corrected Version 2.1.; July 2017. Available online: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf (accessed on 12 November 2022).
Characteristics | Week 8 [n = 22] | Week 16 [n = 19] | |
---|---|---|---|
Weight in kg [mean (SD)] Min–Max | 54.9 (12.7) | 54.4 (9.8) | |
(36.0–92.0) | (36.0–71.1) | ||
Body mass index | Mean (SD) | 20.1 (4.9) | 20.4 (4.1) |
Min–Max | (14.2–32.1) | (14.4–29.3) | |
Cmax (μg/mL) | Median | 18.3 (15.4–22.3) | 18.9 (16.1–21.9) |
Cmin (μg/mL) | Median | 2.08 (1.25–2.90) | 3.41 (2.26–5.07) |
AUC0–24 (ug/h/mL) | Median (IQR) | 184.5 (166.2–223.1) | 240.5 (191.6–275.7) |
Tmax (h) | Median (IQR) | 2 (2.0–4.0) | 2 (2.0–4.0) |
Clearance (L) | Median (IQR) | 2.9 (2.4–3.3) | 2.1 (1.7–2.8) |
Half Life (Hrs) | Median (IQR) | 6.9 (5.8–7.9) | 8.8 (7.4–11.3) |
Therapeutic Range of LZD (10–20 µg/mL) n (%) | |||
Sub Therapeutic (<10) | 1 (4.5%) | 0 | |
Therapeutic (10–20) | 13 (59.1%) | 11 (57.9%) | |
Supra Therapeutic (>20) | 8 (36.4%) | 8 (42.1%) |
Case No | Linezolid Pharmacokinetics | Therapeutic Range | Adverse Events | Outcome at End of Treatment | |||||
---|---|---|---|---|---|---|---|---|---|
Cmax 8th Week | Cmax 16th Week | Cmin 8th Week | Cmin 16th Week | Cmax >20 μg/mL | Cmin >2 μg/mL | At 8th Week | At 16th Week | ||
1 | PK Not done | >20 | PK Not done | >2 | YES | YES | - | Grade I Peripheral Neuropathy | Death at 20 W |
2 | 10 to 20 | 10 to 20 | <2 | >2 | NO | YES | - | - | Cured |
3 | >20 | PK Not done | >2 | PK Not done | YES | YES | - | Optic Neuritis at 12 W | Withdrawn due to ADR |
4 | >20 | 10 to 20 | >2 | <2 | YES | YES | - | Grade I Anemia | Cured |
5 | 10 to 20 | >20 | >2 | >2 | YES | YES | - | Grade I Anemia | Cured |
6 | 10 to 20 | 10 to 20 | <2 | <2 | NO | NO | - | - | Cured |
7 | 10 to 20 | >20 | <2 | >2 | YES | YES | Grade II Peripheral Neuropathy | - | Cured |
8 | >20 | >20 | >2 | >2 | YES | YES | - | Grade III Anemia | Cured |
9 | >20 | >20 | >2 | >2 | YES | YES | Grade I Peripheral Neuropathy | - | Cured |
10 | 10 to 20 | 10 to 20 | <2 | <2 | NO | NO | Grade I Anemia | - | Cured |
11 | 10 to 20 | >20 | <2 | >2 | YES | YES | - | - | Cured |
12 | 10 to 20 | PK Not done | >2 | PK Not done | NO | YES | - | Grade III Anemia | Cured |
13 | 10 to 20 | 10 to 20 | >2 | >2 | NO | YES | - | Grade II Peripheral Neuropathy at 22 W | Cured |
14 | 10 to 20 | 10 to 20 | <2 | >2 | NO | YES | Grade II Anemia at 1 W | - | Cured |
15 | 10 to 20 | 10 to 20 | <2 | >2 | NO | YES | Blurring of vision at 5 W | - | Cured |
16 | 10 to 20 * | >20 | >2 * | >2 | YES | YES | - | - | Cured |
17 | >20 ** | 10 to 20 | >2 ** | >2 | YES | YES | - | Grade III Anemia | Cured |
18 | <10 | 10 to 20 | <2 | >2 | NO | YES | - | - | Cured |
19 | >20 | 10 to 20 | >2 | >2 | YES | YES | Grade I Anemia at 1 W | - | Cured |
20 | 10 to 20 | >20 | <2 | >2 | YES | YES | Grade I Anemia at 2 W | Grade I Anemia | Cured |
21 | >20 | 10 to 20 | >2 | >2 | YES | YES | - | Grade I Peripheral Neuropathy | Cured |
22 | >20 ** | PK Not done | >2 ** | PK Not done | YES | YES | Grade III Anemia at 2 W | Grade IV Anemia 14 W | Cured |
23 | 10 to 20 | PK Not done | >2 | PK Not done | NO | YES | Gd I Peripheral. Neuropathy at 3 W | - | Cured |
Adverse Event | Intense Pharmacokinetic Sampling | Combining Intense and Sparse Pharmacokinetic Results | |||||||
---|---|---|---|---|---|---|---|---|---|
Cmin (μg/mL) | AUC0–24 (μg/mL) | Cmax (μg/h/mL) | |||||||
No | Yes | p-Value | No | Yes | p-Value | No | Yes | p-Value | |
Peripheral Neuropathy | 19 | 4 | 0.54 | 19 | 4 | 0.74 | 38 | 17 | 0.89 |
3.9 ± 2.3 | 3.2 ± 1.1 | 229.8 ± 76.5 | 216.3 ± 42.2 | 21.4 ± 6.1 | 21.2 ± 4.3 | ||||
Anemia | 15 | 8 | 0.24 | 15 | 8 | 0.78 | 23 | 32 | 0.029 |
3.3 ± 1.6 | 4.7 ± 2.8 | 223.6 ± 52.7 | 234.7 ± 101.1 | 19.5 ± 4.5 | 22.6 ± 5.9 | ||||
Blurring of vision | 21 | 2 | 0.94 | 21 | 2 | 0.63 | 53 | 2 | 0.96 |
3.8 ± 2.2 | 3.9 ± 1.4 | 225.2 ± 72.7 | 251.5 ± 64.4 | 21.3 ± 5.6 | 21.5 ± 4.9 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Padmapriyadarsini, C.; Solanki, R.; Jeyakumar, S.M.; Bhatnagar, A.; Muthuvijaylaksmi, M.; Jeyadeepa, B.; Reddy, D.; Shah, P.; Sridhar, R.; Vohra, V.; et al. Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis. Antibiotics 2023, 12, 714. https://doi.org/10.3390/antibiotics12040714
Padmapriyadarsini C, Solanki R, Jeyakumar SM, Bhatnagar A, Muthuvijaylaksmi M, Jeyadeepa B, Reddy D, Shah P, Sridhar R, Vohra V, et al. Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis. Antibiotics. 2023; 12(4):714. https://doi.org/10.3390/antibiotics12040714
Chicago/Turabian StylePadmapriyadarsini, Chandrasekaran, Rajesh Solanki, S. M. Jeyakumar, Anuj Bhatnagar, M. Muthuvijaylaksmi, Bharathi Jeyadeepa, Devarajulu Reddy, Prashanth Shah, Rathinam Sridhar, Vikram Vohra, and et al. 2023. "Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis" Antibiotics 12, no. 4: 714. https://doi.org/10.3390/antibiotics12040714
APA StylePadmapriyadarsini, C., Solanki, R., Jeyakumar, S. M., Bhatnagar, A., Muthuvijaylaksmi, M., Jeyadeepa, B., Reddy, D., Shah, P., Sridhar, R., Vohra, V., & Bhui, N. K. (2023). Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis. Antibiotics, 12(4), 714. https://doi.org/10.3390/antibiotics12040714