Clinical trial NCT01521364: Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Multidrug-resistant Tuberculosis
Extensively Drug-resistant Tuberculosis
Keywords: pharmacokinetic
drug-interaction
linezolid
clarithromycin
Mycobacterium tuberculosis
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2012-01-30
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).
timeFrame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).
Secondary outcomes:
measure: Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl.
timeFrame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline).
measure: Number of Patients With Adverse Events (AEs)
timeFrame: Up to week 6
measure: 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.
timeFrame: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin)
measure: Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva.
timeFrame: At week 3 (after co-administration of 250mg clarithromycin)
Other outcomes:
Locations:
city: Haren
country: Netherlands
facility: Tuberculosis Center Beatrixoord
state: Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Jan-Willem C Alffenaar, PhD, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bolhuis MS, van Altena R, van Soolingen D, de Lange WC, Uges DR, van der Werf TS, Kosterink JG, Alffenaar JW. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J. 2013 Dec;42(6):1614-21. doi: 10.1183/09031936.00001913. Epub 2013 Mar 21.