Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

Study Overview
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Brief Summary
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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.

Official Title
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The Pharmacokinetic Effect of Clarithromycin on the AUC0-12h of Linezolid in Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) Patients

Conditions
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Multidrug-resistant Tuberculosis, Extensively Drug-resistant Tuberculosis

Intervention / Treatment
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* Drug: Addition of different doses of clarithromycin.


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 0mg, 250mg, and 500mg claritromycin<br>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.<br>* 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.<br>* Other names: Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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 | 
| 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis