Linezolid and clarithromycin drug-interaction study in multidrug-resistant and extensively drug-resistant tuberculosis patients.|
|- candidate number||11023|
|- NTR Number||NTR3260|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||25-jan-2012|
|- Secondary IDs||NL35534.042.11 CCMO|
|- Public Title||Linezolid and clarithromycin drug-interaction study in multidrug-resistant and extensively drug-resistant tuberculosis patients.|
|- Scientific Title||The pharmacokinetic effect of clarithromycin on the AUC0-12h of linezolid in multidrug-resistant and extensively drug-resistant tuberculosis patients.|
|- hypothesis||The hypothesis is that clarithromycin significantly increases linezolid serum concentrations.|
|- Healt Condition(s) or Problem(s) studied||Drug interactions, Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB), Linezolid, Clarithromycin|
|- Inclusion criteria||1. Age ≥ 18 years old;|
2. Signed informed consent;
3. Diagnosis of MDR/XDR-TB confirmed with standard microbiological criteria (culturebased, molecular or both).
|- Exclusion criteria||1. Hypersensitivity to linezolid, clarithromycin, erythromycin, or any macrolide antibiotics, or any of the excipients of linezolid or clarithromycin;|
2. Concomitant use with astemizole, cisapride, ergotamine derivatives
(dihydroergotamine, ergotamine), monoamine oxidase inhibitors (phenelzine,
isocarboxazid, selegiline, or moclobemide), pimozide, or terfenadine;
3. Pregnancy or breast-feeding;
5. Concomitant use of other P-gp inhibitors/inducers, e.g. amiodarone, verapamil, digoxin, tipranavir/ritonavir, lovastatin, tariquidar, itraconazole, dipyridamol, erythromycin, ritonavir, quinidine.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-jul-2011|
|- planned closingdate||1-jan-2013|
|- Target number of participants||7|
|- Interventions||Patients will receive 300 mg LIN orally twice a day during six weeks. At week 1 the steady state area under the curve (AUC) 0-12h will be calculated by obtaining samples via an intravenous catheter at 0, 1, 2, 3, 4, 8, and 12 hours after LIN dose. At week 1, also a sample will be subtracted in order to determine P-gp polymorphism, if the subject decided to participate in this part of the study. At this point, 250 mg CLA once a day will be added to the therapy. At Week 3, AUC 0-12h will be measured again. Simultaneously to the seven blood samples, seven saliva samples will be collected if the patient decided to participate to this optional part of the study. Subsequently, the CLA dose will be increased to 500mg once daily. At Week 5, AUC 0-12h will be measured. During a wash-out period of one week the patients will receive LIN, but no CLA. After one wash-out week, at Week 6, a trough LIN serum concentration will be measured.|
|- Primary outcome||The main study parameter is the increase in linezolid AUC0-12h due to a drug-drug interaction with clarithromycin after addition of 250 mg, and 500 mg clarithromycin compared to baseline (0 mg clarithromycin).|
|- Secondary outcome||1. Secondary study parameters consist of monitoring adverse events, i.e. gastro-intestinal side effect for clarithromycin, and
hyperlactatemia, haematological abnormalities (thrombocytopenia or anaemia) and neuropathy for linezolid;|
2. Also the (other) pharmacokinetic parameters of linezolid, clarithromycin and other anti-TB drugs, that are administered as a part of the continuous standard care;
3. Clinical validation of the analysis of linezolid.saliva.
|- Timepoints||Samples will be collected at week 1, 3, 5, and 6.|
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Dr. J.W.C. Alffenaar|
|- CONTACT for SCIENTIFIC QUERIES||Dr. J.W.C. Alffenaar|
|- Sponsor/Initiator ||University Medical Center Groningen (UMCG)|
(Source(s) of Monetary or Material Support)
|University Medical Center Groningen, Department of Hospital and Clinical Pharmacy|
|- Publications||Bolhuis MS, Van Altena R, Uges DR, van der Werf TS, Kosterink JG, Alffenaar JW.
Clarithromycin significantly increases linezolid serum concentrations. Antimicrob Agents Chemother 2010.|
|- Brief summary||We observed increased LIN serum levels in three cases after combining LIN and CLA of which we described one in a case report. Based on the above the hypothesis is formulated that linezolid is a substrate for P-gp mediated interactions.
Patients might benefit from quantifying the interaction between linezolid and clarithromycin, the subject of this study. When quantified this interaction could eventually prevent toxicity, such as time- and dose dependant myelosuppression.
Prevention of toxicity could result in not having to cease one of the few anti-TB drugs that are still effective against
MDR/XDR-TB. It could possibly lead to reduced LIN therapy costs by adjusting LIN dosages in advance. Finally patients
might benefit from a combination of LIN and CLA in the treatment of MDR/XDR-TB due to possible synergistic activity as
shown in in vitro experiments in different Mycobacteria strains.
We suggest to conduct a prospective pharmacokinetic study in MDR- and XDR-TB patients to quantify the above described interaction between LIN and CLA.|
|- Main changes (audit trail)|
|- RECORD||25-jan-2012 - 7-feb-2012|
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