Extensively Drug-resistant Tuberculosis, Multidrug-resistant Tuberculosis
Conditions
Keywords
pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis
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.
Interventions
DRUGAddition 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.
Sponsors
University Medical Center Groningen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Netherlands
Participant flow
Recruitment details
The study was performed at the Tuberculosis Centre Beatrixoord (University of Groningen, University Medical Center Groningen, Haren, The Netherlands). Dates of recruitment: from december 2011 to november 2012.
Pre-assignment details
Not applicatble.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Linezolid + 250mg Claritromycin (wk 2&3) | Protocol Violation | 1 |
| Linezolid + 500mg Claritromycin (wk 4&5) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Clarithromycin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age Continuous | 35 years STANDARD_DEVIATION 17 |
| Region of Enrollment Netherlands | 5 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 5 | 0 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
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).
Time frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0mg Claritrhomycin | Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). | 36.3 mg*h/L |
| 250mg Clarithromycin | Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). | 61.0 mg*h/L |
| 500mg Clarithromycin | Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). | 67.2 mg*h/L |
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.
Time frame: At week 3 (after co-administration of 250mg clarithromycin)
Secondary
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).
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.
Time frame: Up to week 6
Population: No serious adverse events
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0mg Claritrhomycin | Number of Patients With Adverse Events (AEs) | 0 participants |
| 250mg Clarithromycin | Number of Patients With Adverse Events (AEs) | 0 participants |
| 500mg Clarithromycin | Number of Patients With Adverse Events (AEs) | 0 participants |
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.
Time frame: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin)