Introduction
Acquisition of data quantifying the exposure of second-line TB drugs in
pregnant woman treated for rifampicin-resistant TB (RR-TB) is a
priority. Until recently, pregnant and breastfeeding women have
typically been excluded from clinical trials of new drugs, including TB
treatment. (1) The World Health Organization (WHO) currently recommends
individualised treatment regimens with drugs with a preferred safety
profile for pregnant women with RR-TB, (2) although there are limited
human data guiding these recommendations.
Bedaquiline is a group A drug, recommended for inclusion in all RR-TB
treatment regimens, and can be used in pregnant women, although safety
data is lacking. The design of pharmacokinetic studies to explore the
effect of pregnancy on long half-life drugs like bedaquiline is
challenging, as cumulative drug concentrations could mask
pregnancy-related effects on drug exposure. Physiological changes in
pregnancy result in decreased concentrations of many drugs, particularly
in the third trimester. Pharmacokinetics in pregnancy may be complex:
one of the reasons for reduced drug concentrations in pregnancy is the
reduction in plasma concentrations of the two key drug-binding proteins:
albumin and α1-acid glycoprotein. (3) Reduction in these binding protein
concentrations reduces the total (bound and unbound) concentrations of
drugs, but the unbound fraction typically increases, resulting in
unbound drug concentrations that are similar to non-pregnant women. As
only the unbound drug is pharmacologically active, recommendations to
increase the dose of drugs in pregnancy to approximate total
concentrations in non-pregnant women could therefore increase the risk
of toxicity. However, pregnancy also increases several drug clearance
mechanisms, which could reduce unbound drug concentrations. Although
measurement of unbound bedaquiline concentrations is preferable to
rationally optimize dosing in pregnancy (bedaquiline is
>99% protein-bound) (4), an understanding of the effect of
pregnancy on total bedaquiline concentrations would provide a
much-needed foundation to understand the effect of pregnancy on the
unbound fraction.
Data on the secretion of key drugs for RR-TB into human milk are scarce.
The studies describing RR-TB drug exposure in human milk are small with
little or no infant plasma pharmacokinetic data available - the study
designs are also unclear or unstated. Linezolid (5), levofloxacin (6)
and cycloserine (7) penetrate poorly into human milk and exposure to
breastfed infants is therefore likely to be low. Clofazimine, in
contrast, demonstrates effective human milk penetration with skin
discoloration observed in the infants of breastfeeding mothers treated
with clofazimine for leprosy;.(8,9) clofazimine
exposure in human milk in the context of mothers treated for TB is
unfortunately lacking. Animal studies have shown that bedaquiline is
concentrated in rat milk with concentrations 6- to 12- fold higher than
the concentration in maternal plasma (10), but there are currently no
human data available. Information on clinically relevant infant exposure
to RR-TB drugs through breastfeeding with mother-infant pairs has not
been done, and is an important knowledge gap.
An international consensus panel on the inclusion of pregnant and
postpartum women in TB drug trials, convened by the NIH, identified the
safety, tolerability and pharmacokinetics of novel agents and regimens
for treatment of RR-TB as research priorities (11). It is ethically
imperative to study drug dosing and safety in populations where drugs
are used - this has not been done satisfactorily for RR-TB. (12) We
therefore conducted an observational study of bedaquiline exposure in
pregnant and breastfeeding women with RR-TB.