Research Article

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

*Author for correspondence: Tel.: +27 31 260 1963;

E-mail Address: anushka.naidoo@caprisa.org

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

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Veron Ramsuran

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

School of Laboratory Medicine & Medical Sciences, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

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Maxwell Chirehwa

Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Western Cape, South Africa

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Paolo Denti

Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Western Cape, South Africa

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Helen McIlleron

Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Western Cape, South Africa

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Kogieleum Naidoo

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

MRC-CAPRISA HIV-TB Pathogenesis & Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, KwaZulu-Natal, South Africa

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Nonhlanhla Yende-Zuma

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

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Ravesh Singh

Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal, South Africa

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Sinaye Ngcapu

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

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Mamoonah Chaudhry

Department of Immunology & the Institute for Cellular & Molecular Medicine; South African Medical Research Council Extramural Unit for Stem Cell Research & Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa

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Michael S Pepper

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Nesri Padayatchi

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

MRC-CAPRISA HIV-TB Pathogenesis & Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, KwaZulu-Natal, South Africa

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Published Online:6 Dec 2017https://doi.org/10.2217/pgs-2017-0144

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Abstract

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.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 19, No. 1

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History

Received 17 August 2017

Accepted 10 October 2017

Published online 6 December 2017

Published in print January 2018

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Acknowledgements

The authors gratefully acknowledge the study participants for their participation in the IMPRESS pharmacokinetic study; study nurses, counsellors, clinicians, the study co-ordinator D Govender and the IMPRESS study team for their work in the pharmacokinetic study. Special acknowledgement to M Govender and the pharmacy team for support on the study. We thank the following laboratories and laboratory staff; CAPRISA laboratory (N Samsunder, and lab staff), KwaZulu-Natal Research Institute for Tuberculosis and HIV (KRITH) Pharmacology Core and Medical Microbiology Laboratories and Global Clinical & Viral Laboratories, for laboratory support. We thank D Munatsi and P Radebe for data management on the study, and J Bredenkamp (Forest Molecular Genetics Programme, University of Pretoria) for the TaqMan® OpenArray genotyping assay analysis. The Division of Clinical Pharmacology at the University of Cape Town, acknowledges Novartis Pharma for their support of the development of pharmacometric skills in Africa. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. All authors had access to data, commented on drafts and approved the final report. The corresponding author had final responsibility for the decision to submit for publication.

Author contributions

The study concept and design were done by A Naidoo, N Padayatchi, K Naidoo, H McIlleron, MS Pepper and V Ramsuran. Drafting of the manuscript was done by A Naidoo, V Ramsuran, P Denti and M Chaudhry. Statistical analysis: NLME modeling and data analysis were done by P Denti and M Chaudhry. General statistical support was given by N Yende-Zuma. Acquisition, analysis or interpretation of data and critical revision of the manuscript for important intellectual content were done by all the authors.

Financial & competing interests disclosure

This publication was made possible by grant no. 5R24TW008863 from the Office of Global AIDS Coordinator and the US Department of Health and Human Services, NIH (NIH Office of AIDS Research [OAR] and NIH Office of World AIDS Research [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. A Naidoo was the recipient of the University of KwaZulu-Natal College of Health Sciences Scholarship. H McIlleron is supported in part by the National Research Foundation (NRF) of South Africa (grant no. 90729). K Naidoo and N Padayatchi were supported by the Columbia University-South Africa Fogarty AIDS260 International Training and Research Program (AITRP, grant no. D43TW000231). MS Pepper and M Chaudhry 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). V Ramsuran 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, NIH or the Medical Research Council. N Padayatchi is the principal study investigator, on the Improving Retreatment Success Trial (IMPRESS; NCT02114684). Bayer Pharmaceuticals donated the study drug (moxifloxacin) used during the trial. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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