Bedaquiline exposure in pregnancy and breastfeeding in women with
rifampicin-resistant tuberculosis
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.