Elevated Plasma Moxifloxacin Concentrations and <i>SLCO1B1</i> g.−11187G&gt;A Polymorphism in Adults with Pulmonary Tuberculosis

Abstract

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against <i>Mycobacterium tuberculosis</i> 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 (<i>C</i>_max). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC_0-24) and <i>C</i>_max were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.-11187G>A in the <i>SLCO1B1</i> gene (rs4149015) but not by geographic region. The median moxifloxacin AUC_0-24 was 46% higher and the median <i>C</i>_max was 30% higher in 4 (8%) participants who had the <i>SLCO1B1</i> g.-11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC_0-24 from the model, 34.4 versus 23.6 μg · h/ml [<i>P</i> = 0.005, ANCOVA]; median <i>C</i>_max from the model, 3.5 versus 2.7 μg/ml [<i>P</i> = 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 <i>SLCO1B1</i> g.-11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.).