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Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01521364
Recruitment Status : Completed
First Posted : January 30, 2012
Results First Posted : July 1, 2013
Last Update Posted : July 1, 2013
Information provided by (Responsible Party):
JWC Alffenaar, University Medical Center Groningen

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.

Condition or disease Intervention/treatment Phase
Multidrug-resistant Tuberculosis Extensively Drug-resistant Tuberculosis Drug: Addition of different doses of clarithromycin. Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Pharmacokinetic Effect of Clarithromycin on the AUC0-12h of Linezolid in Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) Patients
Study Start Date : December 2011
Actual Primary Completion Date : October 2012
Actual Study Completion Date : November 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
0mg, 250mg, and 500mg claritromycin

Patients receive 300mg linezolid twice a day during entire study. After one week, 250mg claritromycin once daily is added for a duration of two weeks.

After another two weeks, 250mg claritromycin is replaced by 500mg claritromycin once daily for another two weeks.

After this, there is a wash-out period of one week during which no claritromycine is administered.

Drug: Addition of different doses of clarithromycin.

At week 1, 250mg clarithromycin once a day will be added to linezolid therapy during two weeks.

At week 3, 500mg clarithromycin once a day will be added to linezolid therapy during to weeks.

Other Name: Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082

Primary Outcome Measures :
  1. 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).

Secondary Outcome Measures :
  1. 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). ]
  2. 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.

  3. 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) ]
  4. 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.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥18 years old
  • Signed informed consent
  • Diagnosis of MDR/XDR-TB confirmed with standard microbiological criteria (culture-based, molecular or both)
  • Treatment with linezolid 300mg twice daily per os.

Exclusion Criteria:

  • Hypersensitivity to: linezolid, clarithromycin, erythromycin, or any macrolide antibiotics, or any of the excipients of linezolid or clarithromycin.
  • Concomitant use with astemizole, cisapride, ergotamine derivatives (dihydroergotamine, ergotamine), monoamine oxidase inhibitors (phenelzine, isocarboxazid, selegiline, or moclobemide), pimozide, or terfenadine.
  • Pregnancy or breast-feeding.
  • Hypokalemia
  • Concomitant use of other P-gp inhibitors/inducers, e.g. amiodarone, verapamil, digoxin, tipranavir/ritonavir, lovastatin, tariquidar, itraconazole, dipyridamol, erythromycin, ritonavir, quinidine.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01521364

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Tuberculosis Center Beatrixoord
Haren, Groningen, Netherlands
Sponsors and Collaborators
University Medical Center Groningen
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Principal Investigator: Jan-Willem C Alffenaar, PhD, PharmD University Medical Center Groningen
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: JWC Alffenaar, PhD, Pharm D, University Medical Center Groningen Identifier: NCT01521364    
Other Study ID Numbers: NL35534.042.11
2011-000513-39 ( EudraCT Number )
First Posted: January 30, 2012    Key Record Dates
Results First Posted: July 1, 2013
Last Update Posted: July 1, 2013
Last Verified: May 2013
Keywords provided by JWC Alffenaar, University Medical Center Groningen:
Mycobacterium tuberculosis
Additional relevant MeSH terms:
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Tuberculosis, Multidrug-Resistant
Extensively Drug-Resistant Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors