title: Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients.
abstract: The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug-drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid. Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated. Linezolid exposure increased by a median (interquartile range) of 44% (23-102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events. In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug-drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size.
authors.affiliation: University of Groningen, University Medical Centre Groningen, Groningen.
authors.forename: Mathieu S
authors.initials: MS
authors.lastname: Bolhuis
authors.forename: Richard
authors.initials: R
authors.lastname: van Altena
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.forename: Wiel C M
authors.initials: WC
authors.lastname: de Lange
authors.forename: Donald R A
authors.initials: DR
authors.lastname: Uges
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D017291:Clarithromycin; D000069349:Linezolid