Manna Semere Gebreyesus (1), Cathy A. Cluver (2), Eric H. Decloedt (6), Stephen Tong (3), Susan Walker (3), Nicole G.M. Hunfeld (4), HólmfrÃður Helgadóttir (5), Einar S. Björnsson (5), Roeland E. Wasmann (1), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine, University of Cape Town, South Africa (2) Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, 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 (5) Department of internal medicine, Division of Gastroenterology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (6) Division of Clinical Pharmacology, Department of Medicines, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
Objectives: Preterm preeclampsia occurring before 34 weeks of gestation is associated with severe morbidity and mortality. Delivery is the only treatment, which results in iatrogenic prematurity and poor neonatal outcomes (1–3). Preclinical data has shown that esomeprazole can lower concentrations of preeclampsia biomarkers, but a clinical trial (PIE) conducted in South Africa found no change in clinical outcome or biomarker concentrations in women with preterm preeclampsia (4,5). It was hypothesised that the 40-mg daily oral dose was insufficient to achieve therapeutic exposures for preeclampsia (6). Esomeprazole is metabolized by CYP2C19 and by CYP3A4 and, in non-pregnant subjects, repeated dosing causes inhibition of CYP2C19, which decreases clearance and increases bioavailability compared to single dosing (7,8). In pregnancy, CYP2C19 is downregulated, which could decrease esomeprazole clearance, while CYP3A4 is upregulated (9), which could decrease esomeprazole bioavailability and increase clearance, since CYP3A4 is present in the intestines as well as the liver. We aimed to develop a population PK model of esomeprazole (combining the data in pregnant women from the PIE trial with data from healthy, non-pregnant subjects) to investigate the effect of pregnancy and single dose vs repeated dosing on its PK.
Methods: Pregnant patients were treated with Nexium capsules, fasted up to 2 h post dose and were sampled at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 10, and 24 hours after the 1st dose. A control group consisting of data from two studies in healthy, non-pregnant participants receiving a daily dose of 40-mg esomeprazole was obtained (8,10). In the study by Helgadóttir et al., participants were treated with Actavis tablets, fasted up to 2 h post dose and samples taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, and 8 h after the 1st and 5th doses. In the study by Hunfeld et al., participants were treated with MUPS tablets, fed 5 min post dose, and samples taken at 5 min, 1, 2, 3, 4, 5, 6, 7, and 8 h after the 5th dose. Analysis was performed using nonlinear mixed-effects modelling in NONMEM. Allometric scaling was applied to clearance (CL) and volume of distribution (Vd), between-subject and -occasion random effects were assumed to follow a log-normal distribution, and we used a combined additive and proportional error model. The effect of the different studies on bioavailability and clearance were tested with a decrease in objective function value (OFV)>3.84 (p<0.05) for forward addition and an increase in OFV>6.63 (p<0.01) for backward elimination considered statistically significant. A mixture model was used to determine genotypes for the studies where genotyping was not performed.
Results: Data from 59 subjects were included: (i) Ten patients were from the PIE trial: median (range) age of 30 (21-43) years, weight of 99 (56-126) kg, and gestational age of 29 (26-31) weeks; (ii) Thirty participants were from Helgadottir et al., 50% female, median (range) age of 24 (18-46) and weight of 76 (62-107) kg; (iii) Nineteen participants were from Hunfeld et al., 63% female, with median (range) age of 21 (18-27) and weight of 69 (54-89) kg. A two-compartment PK model with first-order elimination and transit absorption best described the data. Typical values of CL of 24.3 L/h for extensive metabolizers and 7.87 L/h for poor metabolizers as well as Vd of 14.4 L were estimated for 70-kg participants. In the pregnant patients, CL was lower by 42.2% compared to the control group after single dose. Within the control group, bioavailability was 33.0% higher while clearance was 54.9% lower on day five compared to day one.
Conclusions: A PK model was identified characterising the PK of esomeprazole in patients with preterm preeclampsia. It was not possible to fully separate the effect of pregnancy/preeclampsia from study due to additional differences between the studies, namely mealtimes and formulation. In pregnant patients, clearance was lower compared to controls after single dose. This could be explained by downregulation of CYP2C19. After repeated dosing in controls, clearance was lower, and bioavailability higher compared to single dose which is probably due to autoinhibition of CYP2C19 which is in line with previous reports (7,11). In pregnant patients, there is already downregulation of CYP2C19 and a reduced clearance, so it is expected that autoinhibition of CYP2C19 with repeated dosing will not cause as much of a change in PK as in non-pregnant patients.
References:
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Reference: PAGE 29 (2021) Abstr 9780 [www.page-meeting.org/?abstract=9780]
Poster: Drug/Disease Modelling - Other Topics