Elevated Plasma Moxifloxacin Concentrations and g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United States enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated by analysis of covariance (ANCOVA) on moxifloxacin exposure and the peak (maximum) concentration (). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC) and were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.-11187G>A in the gene (rs4149015) but not by geographic region. The median moxifloxacin AUC was 46% higher and the median was 30% higher in 4 (8%) participants who had the g.-11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC from the model, 34.4 versus 23.6 μg · h/ml [ = 0.005, ANCOVA]; median from the model, 3.5 versus 2.7 μg/ml [ = 0.009, ANCOVA]). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate the risk associated with the g.-11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.).