Model-Based Efficacy and Toxicity Comparisons of Moxifloxacin for Multidrug-Resistant Tuberculosis. (29th December 2021)

• Record Type: Journal Article
• Authors: Yun, Hwi-Yeol; Chang, Vincent; Radtke, Kendra K; Wang, Qianwen; Strydom, Natasha; Chang, Min Jung; Savic, Radojka M
• Is Part Of: Open forum infectious diseases. Volume 9:Number 3(2022)
• Publication Date: 2021-12-29
• Subjects: lung lesion distribution model -- moxifloxacin -- multidrug resistance tuberculosis (MDR-TB) -- population pharmacokinetics -- QT prolongation model; Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofab660
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-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 integrative model-based approaches in MDR-TB patients. Methods: In total, 113 MDR-TB patients from 5 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 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. Abstract : 400mg, twice-daily dose of MOX could be suggested as an optimal dose for MDR-TB patients evidenced by population PK-lung lesion distribution-QT prolongation model