ECE2021 Presented Eposters Presented ePosters 1: Adrenal and Cardiovascular Endocrinology (8 abstracts)
1Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany; 2Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany; 3Charité-Universitätsmedizin, Berlin, Germany; 4Department of Pharmacology, Clinical Pharmacology, Hospital of the University of Cologne, Cologne, Germany; 5Institute of Mathematics, Universität Potsdam, Potsdam, Germany
Context
Prenatal dexamethasone (Dex) therapy is used in female foetuses with congenital adrenal hyperplasia (CAH) to suppress adrenal androgen excess and prevent virilisation of the external genitalia. The prenatal dexamethasone dose of 20 µg/kg per day has been used for decades in prenatal CAH and is associated with risks for the treated mother and potentially for the unborn child. Despite the high medical need, no prospective, clinical studies had been conducted in order to determine a Dex dose with a scientific rationale.
Objective
We aimed to investigate a rationale of a reduced Dex dose in prenatal CAH therapy based on a pharmacokinetics-based modelling and simulation framework.
Design and methods
Population modelling was applied on a published dexamethasone study to develop a maternal dexamethasone pharmacokinetic model. By simulations, a typical pregnant population was separated into to receive either the 20 µg/kg per day Dex dose or reduced doses. Target maternal dexamethasone concentrations, identified from literature, served as threshold to be exceeded by 90% of patients at steady state to ensure foetal hypothalamic-pituitary-adrenal axis suppression.
Results
A two-compartment dexamethasone pharmacokinetic model was successfully developed. The simulations resulted in 7.5 µg/kg per day to be the minimum effective dose and thus our recommended optimised dose.
Conclusions
Based on our modelling and simulation results, the current experimentally used Dex dose seems 3-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of this reduced dose should be tested in a prospective international clinical trial.