Pharmacokinetics and safety of moxifloxacin; a dose escalation in patients with tuberculosis

Moxifloxacin (MFX) is a fluoroquinolone with a high in vitro and in vivo
bactericidal activity against Mycobacterium tuberculosis. A daily dose of
600-800 mg MFX should be considered for optimal killing of the involved
mycobacteria and suppression of drug resistance, which is higher than the
currently used dose of 400 mg once daily. In general, safety data to support
switching to the suggested higher dose are limited.

Primary Objective:

The main objective of this prospective clinical trial is to compare
pharmacokinetics and safety and tolerability of a standard dose (400 mg) with
an escalated dose of 600 and 800 mg MFX.

Secondary Objectives:

* To evaluate limited sampling strategies based on a pharmacokinetic population
model to predict MFX AUC0-24h
* To evaluate the correlation between MFX concentration (mg/L) and QT interval
(msec)
* To evaluate a genetic risk score for the prediction of MFX induced QT
prolongation

In a prospective clinical trial the pharmacokinetic parameters and
safety/tolerability of three dosages of MFX will be evaluated (400 mg; 600mg;
800mg). For this trial patients will be included, who will receive MFX as part
of their TB regimen, at the Tuberculosis Centre Beatrixoord, University Medical
Center Groningen, The Netherlands. MFX (400 mg) will always be started in the
interest of the patients* TB treatment and not in the interest of the study.

During seven days patients will receive 400 mg MFX once a day. On the 8th day
the dose of MFX will be escalated to 600 mg, and the 15th day the dose of MFX
will be escalated to 800 mg MFX once a day. Once included in the study, each
dosing step is evaluated for proceeding to the next dose. This prevents
potential toxic exposure or increased risks on QT prolongation. The evaluation
criteria are vital signs and pharmacokinetic parameters.

Patients will start on a standard dose of MFX 400 mg once daily. After 8 days
the dose will be increased to 600 mg once daily and on the 15th day of
treatment, the dose of MFX will be escalated to 800 mg. In patients who have
been treated with rifampicin (RIF) in the past three weeks prior to start of
MFX treatment an additional washout period of 3 weeks to reduce the rifampicin
induced enzymatic activity will precede the dose escalation.

Three pharmacokinetic curves will be obtained (400 mg; 600 mg; 800 mg). One
additional blood sample will be obtained to genotype genetic variants that
modulate QT interval. Blood samples will be taken from an indwelling
intravenous (IV) catheter. Every day of treatment a 3-lead ECG will be
recorded. At baseline and on the 7th, 14th, 21st day ambulatory monitoring
(Holter) will be performed. The patient may experience mild discomfort due to
indwelling IV catheter or during (ambulatory) ECG monitoring. The patient may
experience side effects of the study drug (diarrhoea, vomiting) at higher
dosage but these are expected to be rare. The potential benefit for
participating in this study is that treatment can be continued with an
optimized dosage (based on AUC0-24h/MIC ratio) of MFX compared to standard
treatment of 400 mg once daily. The results of this will contribute to
optimization of TB treatment with MFX and may result in a phase III study
comparing standard dosing with individualised dosing.