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/d has been used for decades in prenatal CAH. Despite the risks for the treated mother and potentially for the unborn child, no clinical study or evaluation had been conducted in order to determine a Dex dose with a scientific rationale.
Objective: 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: Data from a published Dex study were used to develop a nonlinear mixed-effects model describing maternal dexamethasone pharmacokinetics (PK). In stochastic simulations (n=1000), a typical pregnant population (n=124) was split into two dosing arms receiving either the traditional 20 μg/kg/d dexamethasone dose or reduced doses between 5 and 10 μg/kg/d. Target maternal dexamethasone concentrations, ensuring foetal hypothalamic‐pituitary‐adrenal axis suppression, were identified from literature and served as threshold to be exceeded by 90% of mothers at steady state.
Results: A two-compartment dexamethasone pharmacokinetic model was successfully developed and evaluated. The simulations, as well as a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/d to be the minimum effective dose and thus our recommended dose.
Conclusions: Based on our modelling and simulation results, the current experimentally used Dex dose seems 3-fold higher than needed, resulting in unnecessary high risks for treated mothers and foetuses. The clinical relevance and appropriateness of this reduced Dex dose during pregnancy will be tested in a prospective international clinical trial.
22 Sep 2021 - 26 Sep 2021