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

Abstract

CONTEXT\nPrenatal 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\xa0µg/kg/d has been used since decades without examination in clinical trials and is thus still considered experimental.\n\n\nOBJECTIVE\nBecause the traditional dexamethasone dose potentially causes adverse 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 framework.\n\n\nMETHODS\nBased on a published dexamethasone dataset a nonlinear mixed-effects 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\xa0µg/kg/d dexamethasone dose or reduced doses between 5 and 10\xa0µg/kg/d. Target maternal dexamethasone concentrations, identified from literature, served as threshold to be exceeded by 90% of mothers at steady state to ensure foetal hypothalamic-pituitary-adrenal axis suppression.\n\n\nRESULTS\nA two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5\xa0µg/kg/d to be the minimum effective dose and thus our suggested dose.\n\n\nCONCLUSIONS\nWe conclude that the current experimentally used dexamethasone dose is 3-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.