Pharmacokinetic and Therapeutic Adaptation of Linezolid in the Treatment of Multi-Resistant Tuberculosis (LINEZOLIDE)
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| ClinicalTrials.gov Identifier: NCT02778828 |
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Recruitment Status :
Completed
First Posted : May 20, 2016
Last Update Posted : February 4, 2019
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Linezolid, primary treatment for MDR-TB combination therapy anti. Until it is the dose of 600 mg x1 / day, rather sensible for most patients is more, which was unanimous. It is true that if a dosage is consensus, it goes without saying, because of the interindividual variability, marked moreover to linezolid, a therapeutic monitoring assay of plasma levels is indispensable for most pharmacological treatments. This therapeutic drug monitoring (TDM) often gives rise, as known, to dosage changes. It turns out that at present no real STP on the basic objectives PK / PD is really made in France in the treatment of tuberculosis (TB) and the bibliography remains rather poor recommendations, and yet all the elements are there: indeed linezolid is an antibiotic whose activity is purely "time-dependent". So one should fulfill 2 PK / PD objectives whose precise boundaries are sometimes still to be determined:
-% T> MIC, or percentage of time spent with plasma concentrations above the minimum inhibitory concentration of linezolid (LNZ) for Mycobacterium tuberculosis. In practice, the residual concentration before the next shot must be> MIC (0.125 to 1 mg / l)
- A fortiori it must also take into account the concentration preventing the appearance of resistant mutants, amounting to 1.2 mg / l
- AUC / MIC> 80, or ratio of the area under the curve (AUC, Area under curve) of plasma concentration versus time and CMI LNZ Until then, and without real bibliographic support, and for the sake of kindness to patients coupled with an economic advantage, the STP consisted of 2 samples, a peak 1:30 after taking (Cmax) and a residual before taking (C min) , after all, to 600mg x1 / 24 correlates well with the AUC (55% peak and 75% for the residual).
Following an observation that 25 to 30% of patients had a C min <1.2 mg / L, and even frequently <0.2 mg / L to 600 mg x 1, with some low peaks and leaving presage an AUC may be insufficient well.
This study is therefore more imperative to be a pharmacological streamlining and ensuring adequate therapeutic monitoring involves both maximum and minimum toxicity efficiency. And in the light of what has already been practiced for other molecules such as mycophenolate for example which is carried AUC or miniAUC for example. It would therefore be in the achievement of AUC in all patients treated with LNZ for TB MDR / XDR for over a week. Achieving this requires AUC obtaining 7 blood samples given day instead of two samples taken at present. Indeed one must have in mind that the peak of rational / residual has become blurred in this context, and that one of the two goals PK / PD is now filled (Cmin> MIC / CMP) but it should not be that not at the expense of the second (AUC). The benefits, direct and indirect are multiple and obtaining them is ensured through this protocol. The study by analyzing individual data will confirm the accuracy of the dose fractionation 300mgx2 / day and at a time to highlight a potential new dosage adjustment that would need to achieve for further study, so a substantial gain in terms of efficacy and toxicity via a suitable therapeutic monitoring. Secondly, determine which collection points, in these patients, these doses will be most interesting to take later in the routine of STP in order to collect less points (eg miniAUC MPA) retaining same statistical power to estimate kinetic parameters, mainly the AUC (eg aminoglycoside also). Finally in a third phase construction on the basis of these individual kinetics of a population pharmacokinetic model with highlighting of population parameters and especially co-related variables explaining the high pharmacokinetic variability and allowing for following patients to determine the individually tailored dose immediately before the first shot and the first assays.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tuberculosis | Drug: Linezolid | Not Applicable |
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| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 31 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Other |
| Official Title: | Determination of Pharmacokinetic and Therapeutic Adaptation of Linezolid in the Treatment of Multi-Resistant Tuberculosis MDR-TB |
| Actual Study Start Date : | November 4, 2015 |
| Actual Primary Completion Date : | December 31, 2017 |
| Actual Study Completion Date : | December 31, 2018 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Patients with Multi-Resistant Tb |
Drug: Linezolid
adjustment of Linezolid of based on the AUC/MIC and % T> MIC for each patient to confirm the appropriateness, in light of the peak and residual, and the interest of the split doses more frequently performed in case of too low residual or toxicity. |
- Air Under the Curve (AUC) of Linezolid concentration [ Time Frame: 30 minutes after oral intaking linezolid ]
- Minimum Inhibitory Concentration (MIC) of Linezolid [ Time Frame: 30 minutes after oral intaking linezolid ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age >18 years
- MDR-TB / XDR
- Treated by Linezolide per os at total daily dose of 600 mg-treatment started for> 7 days
- BMI <35 kg / m²
Exclusion Criteria:
- Age <18 years
- Treatment By Linezolide PO at a dose> or <600mg / d or I.V.
- Treatment Started since <7 days (Plock, 2007)
- Insufficient moderate renal or severe / dialysis
- BMI> 35 kg / m²
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02778828
| France | |
| Sanatorium du Petit Fontainebleau Centre Médical de Bligny | |
| Briis-sous-Forges, Essonne, France, 91640 | |
| Principal Investigator: | Alban LE MONNIER, MD | Groupe Hospitalier Paris Saint-Joseph (FRANCE) |
| Responsible Party: | Groupe Hospitalier Paris Saint Joseph |
| ClinicalTrials.gov Identifier: | NCT02778828 |
| Other Study ID Numbers: |
LINEZOLIDE |
| First Posted: | May 20, 2016 Key Record Dates |
| Last Update Posted: | February 4, 2019 |
| Last Verified: | August 2018 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
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linezolide tuberculosis MDR-TB |
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Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections |
Linezolid Anti-Bacterial Agents Anti-Infective Agents Protein Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |