Effect of genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with tuberculosis

AIM : We assessed the effect of genetic variability in UGT1A and ABCB1 genes on moxifloxacin pharmacokinetics. METHODS : Genotypes for selected UGT1A and ABCB1 SNPs were determined using a TaqMan® Genotyping OpenArray™ and high-resolution melt analysis for rs8175347. A nonlinear mixed-effects model was used to describe moxifloxacin pharmacokinetics. RESULTS : Genotypes of UGT1A SNPs, rs8175347 and rs3755319 (20.6% lower and 11.6% increased clearance, respectively) and ABCB1 SNP rs2032582 (40% reduced bioavailability in one individual) were significantly associated with changes in moxifloxacin pharmacokinetic parameters. CONCLUSION : Genetic variation in UGT1A as represented by rs8175347 to a lesser extent rs3755319 and the ABCB1 rs2032582 SNP is modestly associated with the interindividual variability reported in moxifloxacin pharmacokinetics and exposure. Clinical relevance of the effects of genetic variation on moxifloxacin pharmacokinetic requires further investigation.This publication was made possible by grant number 5R24TW008863 from the Office of Global AIDS Coordinator and the U. S. Department of Health and Human Services, National Institutes of Health (NIH OAR and NIH OWAR). Research reported in this publication was supported by the European & Developing Countries Clinical Trials Partnership (EDCTP) (TA.2011.40200.044), the South African Medical Research Council CAPRISA HIV-TB Pathogenesis and Treatment Research Unit the South African Medical Research Council under a Self-Initiated Research Grant. Study drug was donated by Bayer Pharmaceuticals. AN was the recipient of the University of KwaZulu-Natal College of Health Sciences Scholarship. HM is supported in part by the National Research Foundation of South Africa (Grant Number 90729). KN and NP were supported by the Columbia University-South Africa Fogarty AIDS260 International Training and Research Program (AITRP, grant # D43TW000231). MSP and MC are supported by the University of Pretoria’s Institute for Cellular and molecular medicine and the South African Medical Research Council (University Flagship and Stem Cell EMU awards). VR was supported in part by a research Flagship grant from the South African Medical Research Council (MRC-RFA-UFSP-01- 2013/UKZN HIVEPI). The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the US government, EDCTP, NRF, Fogarty International Center, National Institutes of Health or the Medical Research Council.http://www.futuremedicine.com/loi/pgs2018-12-06hj2018Immunolog