Introduction
Esomeprazole is a proton pump inhibitor which is used for gastric
acid-related disorders in all age groups, including in
pregnancy.1 Its pharmacokinetics is complex. After a
single dose, two-thirds of esomeprazole is metabolized by cytochrome
P450 (CYP) 2C19 to 5-hydroxy- and 5-O-desmethyl esomeprazole and
one-third by CYP3A4 to esomeprazole sulphone.2 CYP2C19
is a polymorphic enzyme, and, after a single dose esomeprazole exposure
is at least three times higher in poor metabolizers compared to
extensive metabolizers.3,4 With repeated dosing,
esomeprazole and esomeprazole sulphone inhibit CYP2C19, thus increasing
exposure due to a lower clearance and higher bioavailability (caused by
decreased first-pass effect).5 This autoinhibition
effect might be more apparent for extensive metabolizers than for poor
metabolizers.2
Esomeprazole pharmacokinetics is unknown during pregnancy but could be
altered due to metabolic changes. During pregnancy, CYP2C19 is
downregulated, which is expected to reduce esomeprazole clearance,
however, this might only be of relevance for extensive metabolizers.
Moreover, CYP3A4 is upregulated during pregnancy, which could result in
a larger proportion of the drug being metabolized by CYP3A4. Since
CYP3A4 is present in the intestines as well as the liver, this could
increase the first-pass effect, decreasing bioavailability and
increasing clearance.6
Preeclampsia is a major complication of pregnancy, a multi-system
disorder where placental dysfunction results in maternal hypertension
and multi-system organ injury.7 An estimated 60,000
maternal and 500,000 fetal deaths annually, of which more than 95% are
in low-and-middle-income countries, are due to
preeclampsia.8,9 There is an urgent need to find
treatment for preterm preeclampsia which slows disease progression and
prevents preterm delivery so that neonatal outcomes can be
improved.10 Esomeprazole has been identified as
potential therapeutic for preeclampsia.11
Preclinical studies showed that esomeprazole lowers placental production
of anti-angiogenic factors thought to play an important role in the
pathogenesis of preeclampsia and improves endothelial
dysfunction.12 Given these findings, a clinical trial
- the PIE trial - investigated the efficacy of a daily 40-mg oral
esomeprazole dose in women with preterm
preeclampsia.13 The trial did not find a significant
difference in clinical outcomes or circulating concentrations of
anti-angiogenic factors among participants taking esomeprazole compared
to those taking placebo. It was postulated that higher doses might be
necessary for treating preeclampsia since concentrations in the pregnant
patients were lower than concentrations which showed efficacy in the
preclinical study.13 The PIE trial generated
pharmacokinetic data of oral esomeprazole in pregnant patients with
preeclampsia, a population in whom esomeprazole pharmacokinetics has not
been previously described.
The aim of this work is to describe the population pharmacokinetics of
oral esomeprazole during pregnancy using data from pregnant women with
pre-eclampsia and healthy, non-pregnant individuals.