TY - JOUR
T1 - Elevated plasma moxifloxacin concentrations and SLCO1B1 g.11187G>A polymorphism in adults with pulmonary tuberculosis
AU - The Pharmacokinetics/Pharmacodynamics Group of Tuberculosis TrialsConsortium
AU - Weiner, Marc
AU - Gelfond, Jon
AU - Johnson-Pais, Teresa L.
AU - Engle, Melissa
AU - Peloquin, Charles A.
AU - Johnson, John L.
AU - Sizemore, Erin E.
AU - Mac Kenzie, William R.
N1 - Publisher Copyright:
© 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/5
Y1 - 2018/5
N2 - 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 (Cmax). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0–24) and Cmax 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 AUC0–24 was 46% higher and the median Cmax 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 AUC0–24 from the model, 34.4 versus 23.6 g · h/ml [P 0.005, ANCOVA]; median Cmax from the model, 3.5 versus 2.7 g/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.).
AB - 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 (Cmax). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0–24) and Cmax 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 AUC0–24 was 46% higher and the median Cmax 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 AUC0–24 from the model, 34.4 versus 23.6 g · h/ml [P 0.005, ANCOVA]; median Cmax from the model, 3.5 versus 2.7 g/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.).
KW - Antibacterial
KW - Fluoroquinolones
KW - Pharmacogenetics
KW - Pharmacokinetics
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U2 - 10.1128/AAC.01802-17
DO - 10.1128/AAC.01802-17
M3 - Article
C2 - 29463526
AN - SCOPUS:85046035594
SN - 0066-4804
VL - 62
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 5
M1 - e01802-17
ER -