Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

Phase 4

Completed

• Conditions: Multidrug-resistant Tuberculosis; Extensively Drug-resistant Tuberculosis
• Interventions: Drug: Addition of different doses of clarithromycin.

• Registration Number: NCT01521364
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2011-09-13
• Study Start: 2011-12
• Study First Submitted QC: 2012-01-25
• Study First Posted: 2012-01-30
• Primary Completion: 2012-10
• Study Completion: 2012-11
• Results First Submitted: 2013-01-17
• Status Verified: 2013-05
• Results First Submitted QC: 2013-05-27
• Last Update Submitted: 2013-05-27
• Results First Posted: 2013-07-01
• Last Update Posted: 2013-07-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 7

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

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
0mg, 250mg, and 500mg claritromycin	Addition of different doses of clarithromycin.	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.

Primary Outcome Measures

Name	Time	Method
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).	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

Name	Time	Method
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).
Number of Patients With Adverse Events (AEs)	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.	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.	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.

Trial Locations

Locations (1)

Tuberculosis Center Beatrixoord; 🇳🇱 Haren, Groningen, Netherlands