Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.

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  • Additional Information
    • Source:
      Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Society for Microbiology
    • Subject Terms:
      Antitubercular Agents/*blood ; Antitubercular Agents/*therapeutic use ; Liver-Specific Organic Anion Transporter 1/*genetics ; Moxifloxacin/*blood ; Moxifloxacin/*therapeutic use ; Tuberculosis, Pulmonary/*drug therapy; Adult ; Africa ; Aged ; Area Under Curve ; Arrhythmias, Cardiac/chemically induced ; Female ; Humans ; Male ; Middle Aged ; Mycobacterium tuberculosis/drug effects ; Polymorphism, Single Nucleotide/genetics ; United States ; Young Adult
    • Abstract:
      Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis 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 ( C max ). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) and C max were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015) but not by geographic region. The median moxifloxacin AUC 0-24 was 46% higher and the median C max was 30% higher in 4 (8%) participants who had the SLCO1B1 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 [ P = 0.005, ANCOVA]; median C max from the model, 3.5 versus 2.7 μg/ml [ P = 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 SLCO1B1 g.-11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.).
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    • Grant Information:
      P30 AG044271 United States AG NIA NIH HHS; P30 CA054174 United States CA NCI NIH HHS; UL1 TR001120 United States TR NCATS NIH HHS
    • Contributed Indexing:
      Keywords: antibacterial; fluoroquinolones; pharmacogenetics; pharmacokinetics
    • Molecular Sequence:
      ClinicalTrials.gov NCT00164463
    • Accession Number:
      0 (Antitubercular Agents)
      0 (Liver-Specific Organic Anion Transporter 1)
      0 (SLCO1B1 protein, human)
      U188XYD42P (Moxifloxacin)
    • Publication Date:
      Date Created: 20180222 Date Completed: 20190715 Latest Revision: 20240628
    • Publication Date:
      20240628
    • Accession Number:
      PMC5923103
    • Accession Number:
      10.1128/AAC.01802-17
    • Accession Number:
      29463526