Model-Based Efficacy and Toxicity Comparisons of Moxifloxacin for Multidrug-Resistant Tuberculosis

Abstract

Background Moxifloxacin (MOX) is used as a first-choice drug to treat multi-drug-resistant tuberculosis (MDR-TB), however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integratvie model-based approaches in MDR-TB patients. Methods In total, 113 MDR-TB patients from five different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment (PTA) value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients. Results The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400 mg twice daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤ 0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV-positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800 mg once-daily dosing regimen, because of the narrow fluctuation of concentrations. Conclusions Our results suggest that a 400 mg twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.

Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis

“…29 We also demonstrated that the LXF MXF and LFX data for MDR-TB patients have been described by a one-compartment model in some previous studies 30,31 and by a two-compartment model in others. 32,33 The reason for this variation is unclear. The differences in the total sample size and number of plasma samples collected during the elimination phases in the studies could be a reason for the observed variations.…”

“…Despite the appeal of a higher starting dose of MXF for optimizing outcomes, our findings may explain a study in Indian MDR-TB patients in a tertiary care center in Mumbai, which found that an increased MXF dosing did not improve treatment outcomes in the presence of low-level resistance to MXF. 38 More interestingly, another recent study by Yun et al 32 suggested a twice 400 mg instead of a single 800 mg MXF is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety. BMI was shown to have a statistically significant influence on V for MXF.…”

Mechanism underlying linezolid-induced peripheral neuropathy in multidrug-resistant tuberculosis

“…A growing number of studies have focused on balancing the efficacy and toxicity of MDR-TB, but no breakthroughs have been made (Bigelow, Tasneen, Chang, Dooley, & Nuermberger, 2020;Yun et al, 2022). We collected primary data from 12 patients with MDR-TB, including gender, age, dose, duration of treatment, presence of peripheral nerve discomfort, self-assessment of pain, etc.…”

QSPR analysis of distance-based structural indices for drug compounds in tuberculosis treatment

“…Levofloxacin was chosen as a versatile antibiotic that works on both Gram-positive and Gram-negative bacteria [26] . A key medication for treating a variety of diseases is the respiratory quinolone moxifloxacin (MOX), particularly for the treatment of tuberculosis and pneumonia [27] , [28] .…”