Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis

Author:

Padmapriyadarsini Chandrasekaran1ORCID,Solanki Rajesh2,Jeyakumar S. M.1ORCID,Bhatnagar Anuj3,Muthuvijaylaksmi M.1,Jeyadeepa Bharathi1,Reddy Devarajulu1,Shah Prashanth2,Sridhar Rathinam4,Vohra Vikram5,Bhui Namrata Kaur6

Affiliation:

1. ICMR-National Institute for Research in Tuberculosis, Chennai 600031, India

2. B.J. Medical College and Hospital, Ahmedabad 380016, India

3. Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, New Delhi 110009, India

4. Government Hospital of Thoracic Medicine, Chennai 600047, India

5. National Institute for Tuberculosis and Respiratory Diseases, New Delhi 110030, India

6. Grand TB Hospital, Mumbai 400015, India

Abstract

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

Funder

United States Agency for International Development

Publisher

MDPI AG

Subject

Pharmacology (medical),Infectious Diseases,Microbiology (medical),General Pharmacology, Toxicology and Pharmaceutics,Biochemistry,Microbiology

Reference24 articles.

1. World Health Organization (2023, January 19). Global Tuberculosis Report 2022, Available online: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022.

2. Regimens to treat multidrug-resistant tuberculosis: Past, present and future perspectives;Pontali;Eur. Resp. Rev.,2019

3. Linezolid for drug-resistant pulmonary tuberculosis;Singh;Cochrane Database Syst. Rev.,2019

4. Linezolid: An effective, safe and cheap drug for patients failing multidrug-resistant tuberculosis treatment in India;Singla;Eur. Respir. J.,2012

5. World Health Organization (2019). WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment.

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