Explaining the failure of moxifloxacin as a short course treatment for tuberculosis

抄録

Background: Moxifloxacin has been considered a promising drug for the treatment of tuberculosis (TB) treatment. However, since its failure in the REMoxTB trial, it is debatable whether 400 mg is appropriate for TB treatment. The objective of the current investigation was two-fold, namely to explain the failure of the REMoxTB trial and illustrate the clinical implications of empirical dose rationale for the use of antibiotic combinations in pulmonary TB. Using pharmacokinetic-pharmacodynamic (PKPD) modelling, we demonstrate how optimal dosing regimens can be selected taking into account both the efficacy and safety profile of moxifloxacin.

Methods: A drug-disease model describing bacterial growth dynamics was used for the analysis of and prediction of microbiological data. M. tuberculosis growth in vivo was characterized under the assumption of a fast and a slow-growing bacterial population. PKPD modelling was used to establish the required exposure to moxifloxacin in the presence of standard of care drugs (i.e. rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA)). The contribution of each companion drug was parameterized as a covariate effect on the potency of moxifloxacin. Simulation scenarios were then evaluated using the baseline characteristics of the REMoxTB trial population to assess the implications of different dosing regimens on the response (i.e. CFU counts) and probability of QT interval prolongation (>10 ms).

Results: The use of a parametric approach reveals that the use of a dose of 400 mg moxifloxacin yields adequate bactericidal activity (80% of the maximum killing rate), but poor sterilizing activity (below 50% of maximum killing rate) due its low potency against the slow-growing bacterial population. An increase in drug levels corresponding to daily doses of 800 to 1200 mg was found to ensure bactericidal and sterilizing effects. However, these doses may not be suitable in clinical practice, as QT interval prolongation of up to 30 ms is likely to occur in most, if not all patients.

Conclusion: Our analysis sheds light on the failure of the REMoxTB trial and offers an opportunity to optimize the dose rationale in future efficacy trials in pulmonary TB. Shortening of treatment requires drugs and dosing regimens with appropriate bactericidal and sterilizing profiles.