Results
Study profile
Bedaquiline pharmacokinetic samples were available from 13 women in the
third trimester of pregnancy, at 30 (IQR: 25 - 37) weeks gestation, six
of whom returned for postpartum sampling at 7 (IQR: 6.5 – 8) weeks.
Seventy-one plasma samples of bedaquiline parent and metabolite
concentration were available for analysis. Participant characteristics
are shown in Table 1. All participants were living with HIV were treated
with antiretroviral therapy (ART), most commonly on nevirapine-based ART
(n=10, 83.3%), but one woman received lopinavir/ritonavir. Serial human
milk samples at the same time-points that plasma was sampled, were
available in two breasfeeding participants. A single random plasma
bedaquiline concentration was available from four infants on the
postpartum PK sampling day, of whom one was breastfed. The serial
post-dose bedaquiline concentrations at each time point are shown in
Table 2.
Pharmacokinetic
model
When we used the published model (14) to predict the expected exposures
in these patients (thus using the original population parameter
estimates and assuming no effect of pregnancy), the model overpredicted
both bedaquiline and M2 concentration on both antepartum and postpartum
visits, as presented in the visual predictive check (VPC) inFigure 1 . The VPC shows that the PK terminal elimination phase
of the participant not on lopinavir/ritonavir were approximately 50%
lower that the model prediction (for both the metabolite and parent) as
illustrated by the deviation of the 50th percentiles
of the observations (red line) from the median of the model predicted
confidence interval (black line). If the pharmacokinetic parameters in
this study were in line with the previous report, we would have expected
to observe higher bedaquiline concentrations. Only the data from the
participant co-administered lopinavir/ritonavir, who had higher
bedaquiline concentrations due to a drug-interaction, was in line with
the model prediction.
When encountered several challenges when attempting to fit the original
model to the current data by re-estimating the parameter values. The
model structure is complex, with multiple disposition compartments, and
the current data did not reliably support the re-estimation of all
parameters - some of the parameter estimates obtained when attempting to
re-fit were unstable and/or implausible. In other words, while the model
could be adapted to fit the study data, this could be achieved in
multiple different ways, e.g. assuming a larger clearance or lower
bioavailability (both pre- and postpartum), but also a larger peripheral
volume of distribution. We experienced further complications when trying
to estimate a significant difference between the two pharmacokinetic
sampling visits, i.e. possibly due to pregnancy status. All the
scenarios were nearly equivalent in terms of goodness of fit, and there
was no meaningful difference in terms of statistical significance, thus
leaving the choice largely in the domain of speculation. Choosing a
different scenario (on which a difference is ascribed to) would imply a
different interpretation of the results, and if the different options
for the model were to be used to predict concentrations and suggest dose
adjustments they could come to very different conclusions. We also
attempted to use a frequentist prior approach (20) to try and stabilise
the parameter estimates, but the results became highly dependent on the
assumptions on the prior precision of each parameter, thus not solving
the problem. For this reason, we decided to simply use the model as
originally published and acknowledge that the concentrations we observed
are lower than expected, assuming that the pharmacokinetics are the same
as non-pregnant patients.
A graphical overview of the infant and human milk data is provided in
Figures 2 and 3, together with the plasma concentrations in the
respective mothers. The PK profiles for bedaquiline and M2 are shown:
maternal plasma concentrations ante- and postpartum, human milk and
infant concentrations. To calculate the human milk to maternal plasma
(M:P) ratio, we used matched milk and plasma samples captured more than
24 hours after the last bedaquiline dose. This was done because during
drug absorption the ratio was rapidly varying and the later samples
better reflect the steady-state equilibrium of bedaquiline. We observed
an average M:P ratio of 24:1 and 5.9:1 for bedaquiline and M2,
respectively. Therefore, assuming a maternal average steady-state
concentration of 0.3 mg/L, the infant bedaquiline dose would be 1.08
mg/kg/day. Similarly, assuming the M2 average steady-state concentration
is 0.1, the infant M2 dose would be 0.09 mg/kg/day. In comparison, a
70-kg individual administered the standard dose of 200 mg bedaquiline
three times a week would result in approximately 1.22 mg/kg/day dose of
bedaquiline.
Bedaquiline and M2 concentrations in the infant who was breastfed were
similar to maternal plasma concentrations, while for the three infants
who were not breastfed, bedaquiline and M2 concentrations were
detectable but lower than maternal plasma values (see Figures 2 and 3).