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Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

Primary Purpose

Multidrug-resistant Tuberculosis, Extensively Drug-resistant Tuberculosis

Status
Completed
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Addition of different doses of clarithromycin.
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multidrug-resistant Tuberculosis focused on measuring pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Tuberculosis Center Beatrixoord

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

0mg, 250mg, and 500mg claritromycin

Arm Description

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.

Outcomes

Primary Outcome Measures

Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).
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.
Number of Patients With Adverse Events (AEs)
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.
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva.
The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.

Full Information

First Posted
September 13, 2011
Last Updated
May 27, 2013
Sponsor
University Medical Center Groningen
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1. Study Identification

Unique Protocol Identification Number
NCT01521364
Brief Title
Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients
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 Type
Interventional

2. Study Status

Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug-resistant Tuberculosis, Extensively Drug-resistant Tuberculosis
Keywords
pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
0mg, 250mg, and 500mg claritromycin
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Addition of different doses of clarithromycin.
Other Intervention Name(s)
Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082
Intervention Description
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.
Primary Outcome Measure Information:
Title
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).
Description
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).
Time Frame
At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).
Secondary Outcome Measure Information:
Title
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).
Title
Number of Patients With Adverse Events (AEs)
Description
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.
Time Frame
Up to week 6
Title
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)
Title
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva.
Description
The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.
Time Frame
At week 3 (after co-administration of 250mg clarithromycin)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan-Willem C Alffenaar, PhD, PharmD
Organizational Affiliation
University Medical Center Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tuberculosis Center Beatrixoord
City
Haren
State/Province
Groningen
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
23520311
Citation
Bolhuis MS, van Altena R, van Soolingen D, de Lange WC, Uges DR, van der Werf TS, Kosterink JG, Alffenaar JW. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J. 2013 Dec;42(6):1614-21. doi: 10.1183/09031936.00001913. Epub 2013 Mar 21.
Results Reference
derived

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Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

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