Discussion
The present study demonstrated significant differences in the BET
pharmacokinetics in DC twin pregnancies. The AUC0-∞and CL/F were significantly lower and higher, respectively, in DC twin
pregnancies compared to singleton and MC twin pregnancies while there
were no differences in the other pharmacokinetic parameters. The
understanding of the pharmacokinetics of drugs during pregnancy is
crucial for the development of appropriate dosage regimens. The clinical
BET pharmacokinetics have been investigated in healthy
adults,20,21,23 as well as in pregnant
women.19,22,11,15
Previous studies developed BET population pharmacokinetic
models19,22 or classical pharmacokinetic
approaches20,21 in both singleton and twin
pregnancies. However, none of these studies evaluated the BET
pharmacokinetics or BET placental transfer in twin pregnancies
discriminated by chorionicity. This study is unprecedented regarding the
BET pharmacokinetic studies in singleton, DC and MC twin pregnancies.
Many demographic and clinical variables such as body composition, blood
volume, hormonal levels, hepatic and placenta metabolism could interfere
with BET pharmacokinetics and explain the findings of the present
study.28,29,11 Furthermore, the influence of the
maternal physiological changes on the kinetics disposition of drugs is
more remarkable in the third trimester of pregnancy and multiple
pregnancies.28–30 It is worth mentioning that all
pregnant women included in this clinical trial were in the last
trimester of their pregnancies.
Few studies that investigated BET elimination in unchanged form in urine
evidenced that the contribution of renal clearance in total clearance is
not significant, supposing that BET is eliminated mainly by its
metabolism.17,23,31 Although pathways that mediate the
BET hepatic metabolism have not been fully established, some studies
have proposed a primary and fundamental role for the cytochrome P450
enzymes, mainly CYP3A4.17,32 Even though some authors
have suggested that BET placental metabolism seems to be low or
negligible,33 others have highlighted the possibility
of increased metabolism due to two or more fetoplacental units in twin
pregnancies.11
Data on the impact of twin pregnancies on BET pharmacokinetics appear to
be contradictory to date. Our data show BET AUC0-∞lower in DC twin pregnancies than in singleton and MC twin pregnancies.
The presence of two fetoplacental units in DC twin pregnancies could
result in a higher metabolism mediated by CYP3A enzymes. Besides,
potentially higher hormone levels in DC pregnancy could induce CYP3A
enzymes in both the placenta and maternal liver and explain these
changes. Also, the increased hepatic flow during pregnancy could rise
the BET clearance and reduce the AUC.
Although some studies have shown significant differences in CL/F or
t1/2 between singleton and twin
pregnancies,19,11 other research groups have not found
similar results.22 Foissac and collaborators found a
28% increase in BET CL/F in twin pregnancies without chorionicity
discrimination compared to singleton pregnancies.19 In
the present study, the BET CL/F values did not differ between MC twin
and singleton pregnancies, but DC twin pregnancies presented a 40%
increase in this pharmacokinetics parameter compared other pregnancies.
Enhanced hepatic metabolism can also explain the pregnancy-related
increase in CL/F.
Our study showed a positive correlation between maternal body mass index
and BET Vd/F. This finding is similar to the Della Torre et al. study,
which showed that maternal lean body weight was a covariate for the Vd/F
using a population pharmacokinetic model.22 Also, the
magnitude of the values of the dose-independent parameters such as CL/F
and Vd/F in the present study were similar to those of previous studies
conducted with pregnant women (Table 2).19,22,11Betamethasone is a lipophilic drug and can bind significantly to
tissue.34 The significant change in pregnant women’s
body size with twin fetuses provides one more possible explanation for
the lower AUC in these pregnancies than singleton ones.
Our study has some strengths. First, few studies have analyzed BET
pharmacokinetics in twin pregnancies, and no study to date has analyzed
BET pharmacokinetic parameters in twin pregnancies separated by
chorionicity. Second, there was only one researcher conducting the
clinical protocol. This ensured the correct interval between the BET
administration and the first blood sample and the serial blood sampling
intervals. Third, before BET pharmacokinetic analysis in the present
study, a BET assay and analytical validation were performed, and the
method showed suitable sensibility, linearity, accuracy and precision
for pharmacokinetics and placental transfer studies in a twin pregnancy.
Our study was not without limitations. Preliminary data on BET placental
transfer can be considered limited mainly due to the low number of
patients in each group and different intervals between drug
administration and delivery. On the other hand, a previous study showed
that BET concentration in cord blood decreases within
days.35 The analysis of umbilical vein/maternal vein
and intervillous space/maternal vein ratios showed that BET
concentration in intervillous space is higher than the fetal
compartments. The inclusion of a more significant number of pregnant
women and applying a protocol with greater precision in the intervals
between the BET administration and the collection of maternal and fetal
blood samples are being carried out to confirm this finding.
In conclusion, this study shows the influence of twin pregnancies on BET
pharmacokinetics, suggesting that the presence of two fetoplacental
units may increase the drug’s metabolism by CYP3A4 enzyme and increase
its elimination. Pharmacokinetic-pharmacodynamic clinical studies are
needed to investigate whether this BET pharmacokinetic changes have
clinical repercussions for the newborns and require dose adjustment in
DC twin pregnancies.
Data availability : The data that support the findings of this
study are available on request from the corresponding author.
Funding statement: The authors thank the São Paulo Research
Foundation (FAPESP) [grant 2017/19256-6] and in part by the Higher
Education Improvement Coordination - Brazil (CAPES) [Finance Code
001].
Authorship statement: G.F.P.R. and A.C.M. designed the clinical
study and wrote the manuscript; G.F.P.R., L.H.C.M. and S.F.F. performed
blood sample collections; G.F.P.R., M.P.P. and V.L.L. performed the BET
quantification in plasma. J.R.L.B and L.V.L. performed the
pharmacokinetic ans statiscal analysis. G.F.P.R., R.C., E.C.D.M., G.D.,
A.C.M, J.R.L.B and L.V.L. performed manuscript review.
Conflict of interest disclosure : The authors have no conflicts
of interest to declare.
Ethics approval statement: Protocol number 8676/2017, of
University Hospital of the Ribeirão Preto Medical School (São Paulo,
Brazil).
Clinical trial registration: The study protocol was registered
on the Brazilian Registry of Clinical Trials (ReBEC,
www.ensaiosclinicos.gov.br) under ID number RBR-2v2mwkz.