Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients

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

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 Overview

• Status: Completed
• Conditions: Multidrug-resistant Tuberculosis; Extensively Drug-resistant Tuberculosis
• Intervention / Treatment: Drug: Addition of different doses of clarithromycin.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Groningen
    • Haren, Groningen, Netherlands
      • Tuberculosis Center Beatrixoord

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

OTHER: 0mg, 250mg, and 500mg claritromycin; 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.; 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.; Other Names: Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Jan-Willem C Alffenaar, PhD, PharmD, University Medical Center Groningen

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ACTUAL): October 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: September 13, 2011
• First Submitted That Met QC Criteria: January 25, 2012
• First Posted (ESTIMATE): January 30, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 1, 2013
• Last Update Submitted That Met QC Criteria: May 27, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: pharmacokinetic; Mycobacterium tuberculosis; linezolid; clarithromycin; drug-interaction
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Clarithromycin
• Other Study ID Numbers: NL35534.042.11; 2011-000513-39 (EUDRACT_NUMBER)