Determination of Pharmacokinetic and Therapeutic Adaptation of Linezolid in the Treatment of Multi-Resistant Tuberculosis MDR-TB
Determination of Pharmacokinetic and Therapeutic Adaptation of Linezolid in the Treatment of Multi-Resistant Tuberculosis MDR-TB
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)
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.
Primary objective :
Determination of 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 toxicity or secondary objective: Determination of points of privileged samples in this context for maximum statistical power and minimal stress for the patient.
- Outlook: Development of a population PK model and determination of co-variables of interest and individualized dosages immediately for the next patients
Methodology :
Prospective, multi-center, non-interventional type of routine care Study duration: 1 day / patient, maximum total duration of recruitment: 6 months, aim 30-40patients included
Acquisition of data:
Additional media (Informed consent, sampling protocol, collection form of biological, clinical and pharmacological patient and treatment)
Development of the study:
Destruction of samples: the samples will not be retained after being used for the study. They will be destroyed in accordance with the rules of good practice research laboratories.
Data: Data include clinical and biological, bacteriological patient. The GHPSJ guarantee that the biological material will be digitally encoded and will not involve direct identifying information of subjects participating in research. The shipment will be made by the sanatorium Bligny staff under the supervision of the investigator within the department (Dr Mathilde Jachym and Damien Le Du).
Ethical aspects: After notification of the CPP Ile de France II, the project will be classified as "research in routine care." The opinion of the CPP Ile de France II will be requested at the meeting of June 2015. The manager research center will be the hospital group Paris Saint-Joseph (GHPSJ). The latter will contract with the SHAM (usual insurer GHPSJ for care and clinical research) to ensure the risk of the blood sample.
The research information will be issued and the signature of the Circular will be collected from the patient. An agreement will be made between institutions, and the GHPSJ Bligny Medical Center, including the logistics of transport and harvest management.
Inclusion Criteria:
Exclusion Criteria: