title: Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis.
abstract: Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories.
authors.affiliation: Department of Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: M S
authors.initials: MS
authors.lastname: Bolhuis
authors.forename: R
authors.initials: R
authors.lastname: van Altena
authors.forename: K
authors.initials: K
authors.lastname: van Hateren
authors.forename: W C M
authors.initials: WC
authors.lastname: de Lange
authors.forename: B
authors.initials: B
authors.lastname: Greijdanus
authors.forename: D R A
authors.initials: DR
authors.lastname: Uges
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: T S
authors.initials: TS
authors.lastname: van der Werf
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017291:Clarithromycin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D016001:Confidence Intervals; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008657:Metabolic Clearance Rate; D023303:Oxazolidinones / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D012463:Saliva / Q000737:chemistry; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D017291:Clarithromycin; D000069349:Linezolid