Moxifloxacin population pharmacokinetics and model-based comparison of efficacy between moxifloxacin and ofloxacin in African patients

Abstract

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 (fAUC0-24) 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 fAUC0-24/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.

Figures

FIG 1

Visual predictive check (VPC) for the final moxifloxacin population pharmacokinetic model. In the upper panel, the lower, middle, and upper solid lines are the 5th, median, and 95th percentiles of the observed plasma concentration, respectively, while the shaded areas are the 95% confidence intervals for the same percentiles of the simulated data. The lower panel shows the fraction of observed data below the lower limit of quantification (LOQ), which is represented by the solid line. The shaded area shows the simulation-based 95% confidence interval around the median of the LOQ data.

FIG 2

Probability of target attainment (target fAUC0–24/MIC ratio ≥ 53) versus Mycobacterium tuberculosis isolate MICs for 400-mg and 800-mg moxifloxacin doses. MDR and XDR data represent MIC distributions from multidrug-resistant and extensively drug-resistant isolates, respectively. PRE-XDR(IR) and PRE-XDR(FR) data represent MIC distributions from isolates resistant to injectables and fluroroquinolones, respectively.

FIG 3

Probability of target attainment (target fAUC0–24/MIC ratio ≥ 53 or 100) versus Mycobacterium tuberculosis isolate MICs for 800-mg ofloxacin dose. MDR and XDR data represent MIC distributions from multidrug-resistant and extensively drug-resistant isolates, respectively. PRE-XDR(IR) and PRE-XDR(FR) data represent MIC distributions from isolates resistant to injectables and fluroroquinolones, respectively.