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Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin-resistant tuberculosis
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  • Richard Court,
  • Kamunkhwala Gausi,
  • Buyisile Mkhize,
  • Lubbe Wiesner,
  • Catriona Waitt,
  • Helen McIlleron,
  • Gary Maartens,
  • Paolo Denti,
  • Marian Loveday
Richard Court
University of Cape Town

Corresponding Author:richard.court@uct.ac.za

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Kamunkhwala Gausi
University of Cape Town
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Buyisile Mkhize
University of Cape Town
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Lubbe Wiesner
University of Cape Town
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Catriona Waitt
University of Liverpool Institute of Translational Medicine
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Helen McIlleron
University of Cape Town
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Gary Maartens
University of Cape Town
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Paolo Denti
University of Cape Town
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Marian Loveday
Medical Research Council of South Africa
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Abstract

Aim We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics and describe bedaquiline exposure in the human milk of mothers treated for rifampicin-resistant TB, where there is no human data available. Methods We performed a longitudinal pharmacokinetic study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at four time-points over six hours in the third trimester, and again at approximately six weeks postpartum. We obtained serial human milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and non-breastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the human milk and plasma bedaquiline assays, and population pharmacokinetic modelling to interpret the bedaquiline concentrations. Results We recruited 13 women, six of whom completed the ante- and post-partum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and post-partum bedaquiline exposures than reported in non-pregnant controls. Bedaquiline concentrations in human milk were higher than maternal plasma (milk to maternal plasma ratio: 24:1). A single random plasma bedaquiline and M2 concentration was available in four infants (median age: 6.5 weeks): concentrations in the one breastfed infant were similar to maternal plasma concentrations; concentrations in the three non-breastfed infants were detectable but lower than maternal plasma concentrations. Conclusion We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in human milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.
31 Oct 2021Submitted to British Journal of Clinical Pharmacology
01 Nov 2021Submission Checks Completed
01 Nov 2021Assigned to Editor
18 Nov 2021Reviewer(s) Assigned
27 Dec 2021Review(s) Completed, Editorial Evaluation Pending
29 Dec 2021Editorial Decision: Revise Major
25 Feb 20221st Revision Received
26 Feb 2022Submission Checks Completed
26 Feb 2022Assigned to Editor
26 Feb 2022Review(s) Completed, Editorial Evaluation Pending
02 Mar 2022Reviewer(s) Assigned
07 Apr 2022Editorial Decision: Revise Minor
14 Apr 20222nd Revision Received
16 Apr 2022Submission Checks Completed
16 Apr 2022Assigned to Editor
16 Apr 2022Review(s) Completed, Editorial Evaluation Pending
27 Apr 2022Editorial Decision: Accept
Aug 2022Published in British Journal of Clinical Pharmacology volume 88 issue 8 on pages 3548-3558. 10.1111/bcp.15380