Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Abstract

h Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC 0 -24 ) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC 0 -24 /MIC ratios of >53 and >100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

“…The frequency of mutation to 3 times the moxifloxacin MIC was (2.11 Ϯ 0.16) ϫ 10 Ϫ5 in repeat experiments. In the HFS-M. abscessus dose-effect studies, the moxifloxacin concentrations measured in each HFS-M. abscessus unit revealed an elimination rate constant (k el ) of 0.11 Ϯ 0.05 h Ϫ1 , which translates to a half-life of 9.8 h, consistent with the moxifloxacin pharmacokinetics in a recent 241-patient clinical study (18). As an example, the r 2 for the intended drug concentrations, exposures, and half-life of the 400-mg standard dose versus the observed concentrations was 0.98, which means the intended pharmacokinetics were recapitulated well.…”

“…Twenty milliliters of 6 log 10 CFU/ml M. abscessus in log phase was inoculated into the peripheral compartment of each of seven hollow-fiber cartridges (FiberCell Systems, Frederick, MD). Doses that mimicked the non-protein-bound plasma 0-to 24-h area under the concentration time curve (AUC 0 -24 ), peak concentrations, and time to maximum concentration achieved in humans treated with moxifloxacin doses of 0, 25, 50, 100, 200, 400, and 800 mg were administered to the central compartment once daily via computerized syringe pumps (18). These exposures were chosen because they represent the range of clinically tolerated doses of moxifloxacin.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…Ofloxacin has been shown to be less efficacious than the others and should be abandoned for tuberculosis therapy. 339 Moxifloxacin, gatifloxacin, and high-dose (ie, 1 g daily for patients weighing >50 kg) levofloxacin display similar early bactericidal activity in drug-susceptible tuberculosis. 340 Sputum culture conversion rates were similar for levofloxacin and moxifloxacin in a small randomised controlled trial in patients with MDR tuberculosis.…”

“…339 However, gatifloxacin poses a risk of hyperglycaemia or hypoglycaemia, so has been removed from the market in many regions. Further study should establish whether higher doses of levofloxacin or moxifloxacin would be more efficacious with acceptable toxicity.…”

Rapid Drug Tolerance and Dramatic Sterilizing Effect of Moxifloxacin Monotherapy in a Novel Hollow-Fiber Model of Intracellular Mycobacterium kansasii Disease

“…We utilized the population pharmacokinetic parameter estimates from 241 patients in South Africa, a country where M. kansasii infection is a problem (1,26,27). These parameters, including betweensubject variability as a percentage of coefficient of variation, are clearance of 10.6 liters/h (18.7%), k a (absorption rate constant) of 1.59 h Ϫ1 (69.9%), and volume of 114 liters.…”