Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling.

Context: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 µg/kg/day has been used since decades without examination in clinical tri als and is thus still considered experimental. Objective: As the traditional dexamethasone dose potentially causes advers e effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation fram ework. Methods: Based on a published dexamethasone dataset, a nonlinear mixed-e ffects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n = 1000), a typical pregnant population (n = 124) was split into two dosing arms receiving either the traditional 20 µg/kg/day dexamethasone dose or reduced doses between 5 and 10 µg/kg/day. Target maternal dexamethasone concentrations, identified from the literature, served as a threshold to be exceeded by 90% of mothers at a ste ady state to ensure foetal hypothalamic-pituitaryadrenal axis suppression. Results: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analys is regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/day to be the minimu m effective dose and thus our suggested dose. Conclusions: We conclude that the traditional dexamethasone dose is three-fo ld higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance an d appropriateness of our recommended dose should be tested in a prospective clinical trial. [ABSTRACT FROM AUTHOR]