Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
JWC Alffenaar, University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT01521364
First received: September 13, 2011
Last updated: May 27, 2013
Last verified: May 2013
  Purpose

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 Intervention Phase
Multidrug-resistant Tuberculosis
Extensively Drug-resistant Tuberculosis
Drug: Addition of different doses of clarithromycin.
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:
  • 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). ] [ Designated as safety issue: Yes ]

    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:
  • 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). ] [ Designated as safety issue: Yes ]
  • Number of Patients With Adverse Events (AEs) [ Time Frame: Up to week 6 ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
  • Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva. [ Time Frame: At week 3 (after co-administration of 250mg clarithromycin) ] [ Designated as safety issue: No ]
    The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.


Enrollment: 7
Study Start Date: December 2011
Study Completion Date: November 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01521364

Locations
Netherlands
Tuberculosis Center Beatrixoord
Haren, Groningen, Netherlands
Sponsors and Collaborators
University Medical Centre Groningen
Investigators
Principal Investigator: Jan-Willem C Alffenaar, PhD, PharmD University Medical Centre Groningen
  More Information

No publications provided by University Medical Centre Groningen

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: JWC Alffenaar, PhD, Pharm D, University Medical Centre Groningen
ClinicalTrials.gov Identifier: NCT01521364     History of Changes
Other Study ID Numbers: NL35534.042.11, 2011-000513-39
Study First Received: September 13, 2011
Results First Received: January 17, 2013
Last Updated: May 27, 2013
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Centre Groningen:
pharmacokinetic
drug-interaction
linezolid
clarithromycin
Mycobacterium tuberculosis

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Extensively Drug-Resistant Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Clarithromycin
Linezolid
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 19, 2014