Clinical Trial: Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Pharmacokinetic Effect of Clarithromycin on the AUC0-12h of Linezolid in Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR

Brief Summary: Future patients might benefit from a combination of linezolid (LIN) and clarithromycin (CLA) in the treatment of Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) due to possible synergistic activity as shown in in vitro experiments in different Mycobacteria strains. The investigators observed increased LIN serum levels in three cases after combining LIN and CLA of which the investigators described one in a case report (Bolhuis et al). The investigators suggest to conduct a prospective pharmacokinetic study in MDR- and XDR-TB patients to quantify the above described interaction between LIN and CLA.

Detailed Summary:
Sponsor: University Medical Center Groningen

Current Primary Outcome: Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin). ]

The AUCs of linezolid will be measured at 3 time points after addition of 3 different clarithromycin dosages.

Samples were obtained before doseing and 1h, 2h, 3h, 4h, 8h, and 12h after administration of linezolid (and claritromycin depending on the period).



Original Primary Outcome: Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin) and week 6 (baseline). ]

The AUCs of linezolid will be measured at 3 time points after addition of 3 different clarithromycin dosages.


Current Secondary Outcome:

  • Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl. [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline). ]
  • Number of Patients With Adverse Events (AEs) [ Time Frame: Up to week 6 ]
    To assess short-term safety and tolerability when combining linezolid (LIN) with clarithromycin (CLA) by monitoring AEs, i.e. gastro-intestinal effects, hyperlactatemia, haematological abnormalities and neuropathy.
  • Pharmacokinetic Parameters, e.g. Tmax, T1/2, Cmax, Cmin, Cl, of Anti-TB Drugs That Are Co-administered as Part of the Continued Standard Care. [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin) ]
  • Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva. [ Time Frame: At week 3 (after co-administration of 250mg clarithromycin) ]
    The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.


Original Secondary Outcome:

  • Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl. [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline). ]
  • Number of patients with/without adverse events (AEs) [ Time Frame: Up to week 6 ]
    To assess short-term safety and tolerability when combining linezolid (LIN) with clarithromycin (CLA) by monitoring AEs, i.e. gastro-intestinal effects, hyperlactatemia, haematological abnormalities and neuropathy.
  • Pharmacokinetic Parameters, e.g. Tmax, T1/2, Cmax, Cmin, Cl, of Anti-TB Drugs That Are Co-administered as Part of the Continued Standard Care. [ Time Frame: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin) ]
  • Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva. [ Time Frame: At week 3 (after co-administration of 250mg clarithromycin) ]
    The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.


Information By: University Medical Center Groningen

Dates:
Date Received: September 13, 2011
Date Started: December 2011
Date Completion:
Last Updated: May 27, 2013
Last Verified: May 2013