title: Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis.
abstract: Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points. The model and LSS were evaluated by analysing the correlation between AUC12h,observedand AUC12h,estimated. In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy. Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r2of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r2of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%. The developed LSS could be used to enable concentration-guided dosing of linezolid.
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Kamp
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Mathieu S
authors.initials: MS
authors.lastname: Bolhuis
authors.affiliation: Division of Infection, Barts Health NHS Trust, London, UK; E. Morelli Hospital AOVV, Reference Centre for MDR-TB and HIV-TB, Sondalo, Italy.
authors.forename: Simon
authors.initials: S
authors.lastname: Tiberi
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Tuberculosis Centre Beatrixoord, Haren, The Netherlands.
authors.forename: Onno W
authors.initials: OW
authors.lastname: Akkerman
authors.affiliation: WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S Maugeri, Care and Research Institute, Tradate, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Centis
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Tuberculosis Centre Beatrixoord, Haren, The Netherlands.
authors.forename: Wiel C
authors.initials: WC
authors.lastname: de Lange
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands; University of Groningen, Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: Jos G
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S Maugeri, Care and Research Institute, Tradate, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Migliori
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands. Electronic address: j.w.c.alffenaar@umcg.nl.
authors.forename: Jan-Willem C
authors.initials: JC
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D005260:Female; D006801:Humans; D007558:Italy; D000069349:Linezolid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D000069349:Linezolid
keywords: Linezolid; Multi-drug resistance; Population pharmacokinetics; TDM; Tuberculosis