Discussion
To our knowledge, this report is the first description of the exposure
of bedaquiline in pregnant women. We found bedaquiline and M2 exposure
in pregnant women to be approximately 50% lower than expected in
non-pregnant patients (14). Although we were underpowered, we found no
significant difference between ante- and postpartum exposures.
There are several possible reasons for the low bedaquiline exposures we
observed in the third trimester. First, increased metabolism of
bedaquiline is a possible explanation - pregnancy is known to induce
CYP3A4, which is the major route of bedaquiline metabolism (21). The
increase in CYP3A4 expression would lead to higher clearance and lower
bioavailability of bedaquiline, since it is present in both entero- and
hepatocytes. Second, pregnancy reduces plasma albumin concentrations, to
which bedaquiline is highly bound (22). The unbound fraction of
bedaquiline may therefore increase, subsequently increasing its
clearance and tissue distribution. In such a scenario, the total
(bound+unbound) concentrations of bedaquiline in plasma would decrease,
but this effect could be counter balanced by the large unbound fraction,
thus maintaining relatively unchanged unbound levels. However,
exploration of free bedaquiline exposure is required before a
recommendation for a dose adjustment can be made. Finally, changes in
body size (and possibly composition) may have affected bedaquiline
disposition, but it is unlikely that the increased weight in pregnancy
affected the exposure of bedaquiline as we used allometric scaling to
account for this in the model, and changes in body size alone are
therefore unlikely to explain the decreased bedaquiline concentrations
we observed.
Similarly, we observed lower-than-expected bedaquiline levels at the
postpartum visit. While it is generally accepted that pharmacokinetic
sampling approximately six weeks postpartum is a reasonable time-point
to allow the physiologic changes related to pregnancy to subside (23),
there are some limitations in using this timeline as a control when
exploring the effect of pregnancy on drugs with a long half-life such as
bedaquiline. Given that the terminal half-life of bedaquiline is more
than five months, (4) any change in pharmacokinetic parameters may only
become apparent on drug exposure after a considerable amount of time,
possibly months. Thus, even if most of the pregnancy effects (if any)
had reversed in the first weeks after delivery, there may not have been
sufficient time for the exposure of bedaquiline to reach a new
equilibrium before the scheduled postpartum pharmacokinetic visit. An
alternative explanation is that adherence could have decreased in the
postpartum period; a systematic review reported poor postpartum
adherence in patients on ART (24). Sub-therapeutic bedaquiline exposures
could affect clinical outcomes and increase the risk of selecting for
drug resistance.
We observed concerningly high concentrations of bedaquiline in the human
milk samples we analysed, markedly higher than the maternal bedaquiline
plasma concentrations, in keeping with the findings of an animal study.
(10) The breastfeeding infant had a plasma bedaquiline concentration
similar to maternal plasma (Figure 2), which could have implications for
infant safety. In a previous animal study, rat pups who were breastfed
to mothers treated with bedaquiline were reported to have low body
weight. (10) In contrast, therapeutic concentrations of bedaquiline in
infants (possible with long half-life drugs, which accumulate slowly,
such as bedaquiline) could potentially be protective in infants exposed
to RR-TB, obviating the need for TB preventive therapy. The three
infants who were not breastfed had sub-therapeutic bedaquiline
concentrations, likely from transplacental exposure, which could select
for drug resistance should the infants develop RR-TB.
The main factors determining the transfer of a drug into human milk are
its physicochemical characteristics (such as lipid solubility and degree
of ionisation at different pH conditions) and its plasma
pharmacokinetics (25). Fat-soluble drugs like bedaquiline cross
lipid-protein cell membranes easily, hence transferring readily into
human milk (25). The ease, with which drug molecules cross cellular
membranes, depends on the drug’s degree of ionisation, which may vary in
different pH conditions. Weak bases like bedaquiline (pKa = 8.9) (26)
tend to be slightly less ionised in plasma compared to milk. This means
that unionised plasma bedaquiline will transfer into human milk, were it
is more likely to be ionised, favouring milk accumulation of the drug
(27). Transfer of drugs into human milk may also be greater in drugs
with a low affinity for maternal plasma proteins, but bedaquiline is
highly protein-bound (>99.9%). (4) An additional factor is
molecular weight, as drugs with low weight (<200 Da) reach
human milk more easily, but the molecular weight of bedaquiline is
555.504 Da (28). Drugs, which have a long plasma half-life and therefore
accumulate, such as bedaquiline, are prone to transfer into human milk
compared with molecules which are cleared rapidly. The high
concentration of bedaquiline in human milk suggests that the mammary
glands could be a clearing site for bedaquiline. Excretion could be
significant, since, on average, a baby consumes about 0.15 L/kg/day of
human milk (18). Moreover, bedaquiline metabolism in breast tissue
cannot be excluded, as there are contradictory reports on the expression
of CYP3A4 in human breast tissue. (29–31)
Our study has several limitations. First, we did not measure unbound
bedaquiline concentrations or albumin levels, so we are unable to
conclusively determine if the reasons for the low concentrations
observed are related to protein binding. Second, there was a high rate
of participant loss to follow up, which limited our sample size, as many
participants were unable for logistical reasons, to complete the
postpartum PK sampling day. Third, PK sampling was not always performed
on a day when bedaquiline was scheduled to be administered (dosing is
three times a week). Although this was accounted for in our modelling,
considering we did not use an adherence measure, the date and time of
the last bedaquiline dose was obtained via participant self-report,
which could be unreliable.
We report low exposures of bedaquiline in this series of pregnant women
treated for RR-TB. Future studies should analyse bound and unbound
bedaquiline concentrations with adherence measures to better understand
the effect of pregnancy on bedaquiline exposure, and assess whether a
different dosing recommendation for bedaquiline in pregnancy is
warranted. Bedaquiline appeared to significantly accumulate into human
milk, which could be an exposure risk for breastfeeding babies and
should therefore be investigated.
Acknowledgments
The authors would like to acknowledge the participants who volunteered
for the study, and Sindisiwe Hlangu for her assistance with study
implementation.
Conflicts of interest
The authors declare no conflicts of interest
Funding
The University of Cape Town Clinical PK Laboratory is supported in part
via the Adult Clinical Trial Group (ACTG), by the National Institute of
Allergy and Infectious Diseases (NIAID) of the National Institutes of
Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701;
as well as the Infant Maternal Pediatric Adolescent AIDS Clinical Trials
Group (IMPAACT), funding provided by National Institute of Allergy and
Infectious Diseases (U01 AI068632), The Eunice Kennedy Shriver National
Institute of Child Health and Human Development, and National Institute
of Mental Health grant AI068632. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the sponsors. Catriona Waitt is supported by a
Wellcome Clinical Research Career Development Fellowship 222075/Z/20/Z.
Data availability
The data that support the findings of this study are available from the
corresponding author upon reasonable request.