Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

Abstract

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by doseand 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%, p50.043) after coadministration of 500 mg clarithromycin (n55) 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. @ERSpublications Clarithromycin significantly increased linezolid serum exposure in multidrug-resistant tuberculosis patients

Evaluation of macrolides for possible use against multidrug-resistantMycobacterium tuberculosis

“…Furthermore, a decrease in mortality in murine infection models [39,60] and synergistic effects when CLR was combined in vitro with second-line anti-TB drugs [36,37,40,57,73] were seen. Also, an interaction was reported in a clinical study [61], suggesting an increase of LZD serum concentration when combined with CLR.…”

“…One study described the influence of CLR on LZD exposure in five MDR-TB patients. While 250 mg CLR once daily had no statistically significant effect, 500 mg of CLR significantly increased LZD serum exposure by a median of 44% compared with baseline [61]. Another retrospective study reported that when CLR was included in a salvage regimen, this did not necessarily result in improved culture conversion [62].…”

“…However, it should not be counted as or included among the drugs making up the standard regimen [4]. Furthermore, besides the observed in vitro synergistic effect of CLR and LZD [57], one clinical study also described an interaction between CLR and LZD suggesting an increase of LZD serum concentration when combined with CLR [61]. This could potentially be cost saving, because a reduced dose of the very expensive drug LZD can be used to reach similar drug exposure and this should be verified on a case by case basis by measuring LZD levels.…”

“…The observed interaction also has a downside since the occurrence of major adverse events associated with LZD, such as anaemia and peripheral neuropathy, are higher when serum concentrations of LZD are higher. Therefore, this necessitates caution when prescribing CLR simultaneously with LZD [61].…”

Pulmonary Tuberculosis Management: 2015 Update

“…Diacon, et al 48 (Continue) that a linezolid dose between 300 and 600 mg per day is adequate to treat MDR-/XDR-TB when added to OBR [52][53][54][55][56][57][58][59][60][61] .…”