Manna Semere Gebreyesus (1), Cathy A. Cluver (2), Eric H Decloedt (3), Stephen Tong (3), Susan Walker (3), Nicole G.M. Hunfeld (4), Roeland Wasmann (1), Paolo Denti (1)
(1) Department of medicine, Division of clinical pharmacology, University of Cape Town, South Africa; (2) Department of obstetrics and Gynaecology, Stellenbosch University, South Africa; (3) Department of obstetrics and Gynaecology, University of Melbourne, Australia; (4) Department of Pharmacy and Intensive Care, Erasmus University Rotterdam, Netherlands
Introduction: Preeclampsia is a progressive pregnancy specific condition that presents as new onset hypertension and signs of organ damage such as proteinuria. It presents in the third trimester after 20 weeks of gestation and is called ‘early-onset’ when it occurs before 32 weeks (1). Severe preeclampsia can progress quickly to become life threatening, and there is no treatment apart from delivery. However, delivery is problematic in early-onset preeclampsia since it results in iatrogenic foetal prematurity and is associated with poor neonatal outcomes especially in developing countries with poor resources (2,3). The pathophysiology of preeclampsia has been identified to arise from a hypoxic placenta due to poor placentation which results in angiogenic imbalance. Soluble fms-like tyrosine kinase (sFlt1) and soluble endoglin (sEng) are biomarkers that are thought to play key roles in preeclampsia (4,5). Preclinical data showed that esomeprazole (ESO), a proton pump inhibitor, can lower sFlt1 and sEng concentrations (6). A randomised controlled trial, the PIE trial, was conducted in South African women diagnosed with early-onset preeclampsia to investigate efficacy, but it found no change in clinical outcome nor a change in sFlt1 and sEng concentrations. It was hypothesised that the 40 mg daily oral dose used was insufficient to achieve therapeutic exposures (7). Esomeprazole is predominantly metabolized by CYP2C19, a polymorphic enzyme, to metabolite 5-hydroxy esomeprazole (HYD) and 5-O-desmethyl esomeprazole, and by CYP3A4 to metabolite esomeprazole sulfone (SULF). CYP2C19 activity is expected to decrease while CYP3A4 activity is expected to increase in pregnancy (8).
Objectives:
- Develop a population PK model of esomeprazole in early-onset preeclampsia using PK data from the PIE trial;
- Investigate changes in metabolic pathways in pregnancy compared to healthy, non- pregnant subjects
Methods: PK data from 10 patients in the treatment arm of the PIE trial, median (range) age of 30 years (21-43), a weight of 98.8 kg (56-126), and gestational age of 29 weeks (26-31), were included. Patients were treated with 40 mg esomeprazole daily and were sampled at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 10, and 24 hours after the first dose. For healthy, non-pregnant subject (controls), a pooled PK dataset was used from two studies where subjects were given 40 mg esomeprazole daily and were sampled at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 hours after the first dose (9,10). The pooled control data consisted of PK data from 26 subjects with median (range) age of 21 (18-27) years and weight 69 (54-89) Kg. Analysis of the PIE PK data was done using nonlinear mixed effect modelling with allometric scaling on clearance (CL) and volume of distribution (Vd). Non compartmental analysis of parent and metabolites from PIE and controls was performed using Pkanalix (Lixoft®) and metabolite to parent AUC ratios (AUCm/p) were calculated for HYD (AUCHYD/ESO) and SULF (AUCSULF/ESO) metabolites (the control group dataset did not have the desmethyl metabolite data). The Mann-Whitney U test was used to compare AUCHYD/ESO and AUCSULF/ESO ratios between the PIE group and the control group at a significance level of 0.05.
Results: A one compartment PK model with first-order elimination and transit compartment absorption best described the PIE data. Typical values of 19.4 L/h for CL and 42.2 L for Vd were estimated using this model. The AUCSULF/ESO ratio was significantly higher in the PIE group, median (range) 2.22 (1.01 – 3.5), compared to the control group, 1.31 (1.09 – 1.5), p<0.05. AUCHYD/ESO ratio in the PIE group was not significantly different from controls, 0.06 (0.06 – 0.15) versus 0.13 (0.05 – 0.26), respectively.
Conclusions: We propose a PK model characterising the PK of esomeprazole in pregnant patients with early-onset preeclampsia. Genotype information was not available in this study, thus making comparisons difficult, however, the estimated CL and Vd are higher than those previously reported for healthy non-pregnant subjects. The AUCSULF/ESO ratio was higher in pregnancy which could be explained by the expected upregulation of CYP3A4 and downregulation of CYP2C19.
References:
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[10] Hunfeld NG, Touw DJ, Mathot RA, Van Schaik RH, Kuipers EJ. A comparison of the acid-inhibitory effects of esomeprazole and rabeprazole in relation to pharmacokinetics and CYP2C19 polymorphism. Aliment Pharmacol Ther. 2012;35(7):810–8.
Reference: PAGE () Abstr 9509 [www.page-meeting.org/?abstract=9509]
Poster: Drug/Disease Modelling - Other Topics