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.