Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

NCT01521364 | Completed Phase 4 Results

• 2 other identifiers: NL35534.042.112011-000513-39
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Multidrug-resistant Tuberculosis; Extensively Drug-resistant Tuberculosis

Keywords

pharmacokinetic; drug-interaction; linezolid; clarithromycin; Mycobacterium tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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

• 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)

Study Arms (1)

0mg, 250mg, and 500mg claritromycin

OTHER

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.

Interventions

Addition of different doses of clarithromycin. DRUG

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.

Also known as: Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082

0mg, 250mg, and 500mg claritromycin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

Tuberculosis Center Beatrixoord

Haren, Provincie Groningen, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 23520311 DERIVED

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis

Interventions

Clarithromycin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. J.W.C. Alffenaar
• Organization: University of Groningen, University Medical Center Groningen

j.w.c.alffenaar@umcg.nl

+31-50-3614070

Study Officials

• Jan-Willem C Alffenaar, PhD, PharmD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD, Pharm D

Study Record Dates

• First Submitted: September 13, 2011
• First Posted: January 30, 2012
• Study Start: December 1, 2011
• Primary Completion: October 1, 2012
• Study Completion: November 1, 2012
• Last Updated: July 1, 2013
• Results First Posted: July 1, 2013

Record last verified: 2013-05

Locations

NL (1)