Discussion
We developed a population pharmacokinetic model to describe the
pharmacokinetics of esomeprazole in pregnant women with preeclampsia. To
our knowledge, this is the first population pharmacokinetic model
describing esomeprazole pharmacokinetics during pregnancy. We found that
clearance was 42.2% (14.9% – 61.6%) lower in pregnant women with
preterm preeclampsia after a single dose of esomeprazole compared to
non-pregnant individuals. In non-pregnant individuals, clearance was
54.9% (48.2% – 63.5%) lower in extensive metabolizers and
bioavailability was 33% (10.0% – 52.0%) higher after repeated dosing
compared with single dose.
Increases in concentration of hormones such as oestrogen and
progesterone during pregnancy could downregulate
CYP2C19.6,21 The lower clearance in the pregnant
patients is likely to be due to this downregulation of CYP2C19. Previous
studies reported that CYP3A4 is upregulated during
pregnancy,21,22 and since CYP3A4 is abundantly present
in the gut one would expect a lower bioavailability. We did not find
this effect in our model.
The lower clearance in extensive metabolizers in non-pregnant
individuals with repeated esomeprazole dosing is likely to be due to
auto-inhibition of CYP2C19 while the higher bioavailability could be
because of a decreased first-pass effect associated with CYP2C19
auto-inhibition.2,5 Moreover, it has previously been
reported for omeprazole that a decrease in intragastric acidity with
repeated doses could lower its degradation in the stomach, improving its
absorption.23 Hence, with repeated administration of
esomeprazole, there could be improved bioavailability due to increase in
pH and lower degradation in the stomach.
Esomeprazole disposition has mostly been described in literature with
one-compartment kinetics for oral data and two-compartment kinetics for
IV data.24,25 Two-compartment disposition showed
better fit in our model, similar to a model by Standing et
al .26 We estimated a typical clearance which was more
than three times higher in extensive metabolizers compared to poor
metabolizers This finding is consistent with previous reports that poor
metabolizers have up to three times higher exposure than extensive
metabolizers.3,4 Our estimate of clearance in poor
metabolizers agrees with models by Nagase et
al .24 and Standing et al .26The typical central apparent volume of distribution of 14.9 L in our
study is similar to that found in healthy individuals
(~16 L).24,27 High variability in
speed of absorption was observed in our model, likely due to differences
in gastric acidity between-individuals and
occasions.24
Our study shows that esomeprazole clearance is lower during pregnancy
which is probably due to CYP2C19 downregulation. This has several
implications: first, metabolism during pregnancy may be more dependent
on CYP3A4, which could mean there is less need for CYP2C19 genotyping
during pregnancy, which has previously been suggested for proton pump
inhibitors due to genotype-dependent variations in exposure and
therapeutic/adverse outcomes.28 This could also mean
less drug-drug interactions that involve CYP2C19. Second, the
nonlinearity in esomeprazole pharmacokinetics with repeated dosing and
with dose increases would be expected to be less in pregnancy.
Specifically, the increase in exposure with repeated dosing, which is
due to CYP2C19 autoinhibition, would not be expected to be as high as in
non-pregnant. Esomeprazole exposure increases more than dose-dependently
with dose increases above 20 mg, due to saturation of CYP2C19-based
clearance and first pass effect.5,29 We don’t expect
as high of a nonlinear increase in exposure during pregnancy since
metabolism could be CYP3A4-dependent, which is generally considered
linear.5,24,29
It was a limitation in our study that we couldn’t isolate the actual
effect of pregnancy and repeated dosing because there were other factors
that were different between the studies, such as mealtimes and
formulation, which could affect the absorption of esomeprazole. However,
we believe that with the available data, our model can adequately
describe changes during pregnancy and repeated dosing. Only single dose
data was available for pregnant patients and effect of repeated dosing
during pregnancy could not be investigated. Nevertheless, esomeprazole
metabolism seems to be less dependent on CYP2C19 during pregnancy, and
we expect pregnant patients to have similar exposure after repeated
doses as after single dose.
We used the first oral esomeprazole data from pregnant patients
generated by the PIE trial to describe esomeprazole pharmacokinetics in
pregnancy. PIE had found similar esomeprazole exposure in pregnant women
to non-pregnant. In our model, we identified a lower clearance in
pregnant women, but no significant change in bioavailability. Richer
data from pregnant patients including healthy, non-pregnant controls and
with CYP2C19 genotyping are needed to further investigate this. PIE
reported no clinical benefit of esomeprazole for preeclampsia.
Preclinical studies are needed to identify the pharmacodynamic target
for preeclampsia and how esomeprazole acts on this target. Further
clinical trials are also needed to investigate whether the preclinical
efficacy can translate into human efficacy and our model can help to
inform the design of these studies as well as to establish the
pharmacokinetic metric that relates with pharmacodynamic markers for
preeclampsia.