Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

Extensively Drug-resistant Tuberculosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01521364
• Other study ID #: NL35534.042.11
• Secondary ID: 2011-000513-39
• Status: Completed
• Phase: Phase 4
• First received: September 13, 2011
• Last updated: May 27, 2013
• Start date: December 2011
• Est. completion date: November 2012

Study information

• Verified date: May 2013
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: November 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Extensively Drug-resistant Tuberculosis
• Multidrug-resistant Tuberculosis
• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

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.

Locations

Country	Name	City	State
Netherlands	Tuberculosis Center Beatrixoord	Haren	Groningen

Sponsors (1)

Lead Sponsor	Collaborator
University Medical Center Groningen

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).	Yes
Secondary	Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl.		At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline).	Yes
Secondary	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.	Up to week 6	Yes
Secondary	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.		At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin)	Yes
Secondary	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.	At week 3 (after co-administration of 250mg clarithromycin)	No