Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

University Medical Center Groningen7 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Multidrug-resistant Tuberculosis Extensively Drug-resistant Tuberculosis

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Secondary Outcomes

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).

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

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)

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)