pharmacokinetics and toxicity of linezolid in MDR-TB patients

MDR-TB is a potentially lethal form of tuberculosis, associated with prolonged
suffering, prolonged treatment, and drug toxicity. In MDR-TB, sub-therapeutic
drug plasma levels should be avoided as otherwise additional drug resistance
due to inappropriate dosing and subsequent selection of less susceptible
strains may ensue. In the limited number of potentially helpful agents,
linezolid has emerged as a potentially helpful component, but toxicity is an
important concern.

In Beatrixoord (UMCG, Haren, the Nertherlands), a specialised centre for
treatment of MDR-TB in the Netherlands linezolid has been evaluated in the
initial treatment of some MDR-TB patients. From a preliminary evaluation, it
appeared that 3/12 patients developed severe toxicity which led to
discontinuation of therapy(1). Recently a case series of 3 patients being
treated with linezolid was reported. The authors showed that a 50% dose
reduction of linezolid led to reduced toxicity. Although the authors suggested
that efficacy was maintained they failed to produce evidence for this claim
(2). As patients with MDR-TB are typically treated with combinations of drugs,
and as response to treatment is a multifactorially determined event, only PK/PD
data help to decide whether single agents in a drug combination contribute to
total effectiveness. Efficacy of linezolid is correlated with AUC0-24h/MIC
(2). To perform a dose reduction without losing efficacy it might be necessary
to measure the AUC0-24h/MICratio after the dose reduction. Particularly in case
of MDR-TB sub-therapeutic and toxic plasma levels should be avoided.

To study the pharmacokinetics of linezolid in MDR-TB patients, specifically in
the relationship to dose, treatment duration and toxicity.

This study is designed as pharmacokinetic study: on day 2 and day 4, on each
day 6 blood draws will be taken to evaluate whether target blood concentrations
can be achieved with the two dosing regimens studied - i.e., the
standard-recommended dosing of 600 mg bid, and 300 mg bid. Plasma samples are
analysed using a liquid chromatography-tandem mass spectrometry(3;4). The
target-blood concentrations of linezolid assumed to be effective are based on
resistance break-off data obtained from the RIVM. The attending physician can
decide based on individual results to continue treatment with 600mg or 300mg
b.i.d. Monitoring for side effects (affecting blood, nervous- and GI system) is
continued during treatment with linezolid.

n/a

There is a potential benefit for the subjects in this study. As
pharmacokinetics of linezolid are evaluated in each individual the decision to
reduce dosage of linezolid or stop treatment can be performed based on
individual pharmacokinetic findings. As the AUC0-24h /MIC of linezolid is
correlated with a favourable outcome therapy is optimised in every individual
patient. An potential benefit is monitoring of nervous system side effects
with EMG and VEP monitoring. Side effects are now detected before becoming
clinical relevant. The burden for participation is sequential venous blood
sampling; six samples (each 2 mL) for the two dosing regimens are required;
i.e., 24 mLs of blood to be drawn in total. For the purpose of this study, an
indwelling intravenous cannula will need to be inserted. Patients may
experience some discomfort of the procedure of sampling. The benefit probably
outweighs the burden and risk.