Pharmacokinetics and Safety of Moxifloxacin

Study Overview
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Brief Summary
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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 (600 mg; 800 mg) of moxifloxacin (MFX). This clinical trial will provide important safety information on MFX in a higher dosage in TB patients.

Detailed Description
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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. For this purpose, twenty tuberculosis 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.

Official Title
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Pharmacokinetics and Safety of Moxifloxacin; a Dose Escalation in Patients With Tuberculosis

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with TB, with Mycobacterium tuberculosis (or M. africanum) by culture Starting treatment with MFX in a dose of 400 mg as part of their TB treatment Exclusion Criteria: Contra-indication for MFX Baseline QTc-interval > 450 msec History of resuscitation History of ventricular tachycardia (including Torsades de Pointes) Family history of sudden cardiac death or Torsades de Pointes Additional risk factors for Torsades de Pointes (including known heart failure, Left ventricular hypertrophy) Use of concomitant treatment with QT/QTc prolonging drugs (including anti-dysrhythmics class IA and III, antipsychotics, tricyclic antidepressants or the antihistaminic drug terfenadine) Abnormal electrolytes (K, Mg, Na, Ca) Abnormal cardiac repolarisation on screening/baseline ECG History of adverse events to fluoroquinolones HIV co-infection RIF treatment during last 3 weeks before start of the study. After a washout period of 3 weeks the patient can be included.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moxifloxacin<br>Moxifloxacinin escalating dose | Drug: Moxifloxacin<br>* 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.<br>* Other names: MFX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) | % of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin | 7 days post dosage | 
| Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis | % of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 400 mg (i.e. 7 day post dosage) moxifloxacin. | 7 days post dosage | 
| Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio | % of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin | 7 days post dosage | 
| Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance | % of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin | 7 days post dosage | 
| % of patients having adverse effects, including QT interval prolongation, hypersensitive reactions, diarrhoea, vomiting and hepatic or renal injury | QT interval in msec Percentage of patients developing hepatic toxicity grade ≥ 2 or 3 Common Toxicity Criteria (CTC) Percentage of patients developing renal toxicity grade ≥ 2 CTC | up to 21 days | 
| Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) | % of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin | 14 days post dosage | 
| Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) | % of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 days post dosage | 
| Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis | % of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin. | 14 days post dosage | 
| Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis | % of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 800 mg (21 days post dosage) moxifloxacin. | 21 days post dosage | 
| Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio | % of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin | 14 post dosage | 
| Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio | % of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 post dosage | 
| Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance | % of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 600 mg (i.e. 14 days post dosage) and moxifloxacin | 14 days post dosage | 
| Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance | % of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 days post dosage | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated. | Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 400 mg (i.e. 7 days post dosage)moxifloxacin | 7 days post dosage | 
| Correlation between MFX concentration (mg/L) and QT interval (msec) | Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin | 7 days post dosage | 
| Correlation of drug exposure (AUC) and adverse effects | vomiting and diarrhoea QT interval (msec) | up to 21 days | 
| Correlation between the genetic risk score and MFX induced QT prolongation |  | up to 21 days | 
| Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated. | Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin | 14 days post dosage | 
| Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated. | Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 days post dosage | 
| Correlation between MFX concentration (mg/L) and QT interval (msec) | Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin | 14 days post dosage | 
| Correlation between MFX concentration (mg/L) and QT interval (msec) | Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 days post dosage | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, Moxifloxacin, Pharmacokinetics, Safety