Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Graduate Research Training Program PharMetrX, Berlin, Germany.
Eur J Endocrinol. 2021 Aug 3;185(3):365-374. doi: 10.1530/EJE-21-0395.
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 trials and is thus still considered experimental.
As 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.
Based 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 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 steady state to ensure foetal hypothalamic-pituitary-adrenal axis suppression.
A 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 µg/kg/day to be the minimum effective dose and thus our suggested dose.
We conclude that the traditional dexamethasone dose is three-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.
先天性肾上腺皮质增生症女性胎儿接受产前地塞米松治疗，以抑制雄激素过多并防止外生殖器男性化。几十年来，传统的地塞米松剂量 20μg/kg/天一直未在临床试验中进行检查，因此仍被认为是实验性的。
由于传统的地塞米松剂量可能会对治疗的母亲和胎儿产生不良反应，我们旨在根据基于药代动力学的建模和模拟框架，为产前先天性肾上腺皮质增生症治疗中减少地塞米松剂量提供依据。
基于已发表的地塞米松数据集，开发了一个描述母体地塞米松药代动力学的非线性混合效应模型。在随机模拟（n=1000）中，将一个典型的孕妇人群（n=124）分为两个剂量组，分别接受传统的 20μg/kg/天地塞米松剂量或 5-10μg/kg/天地塞米松剂量。目标母体地塞米松浓度来源于文献，作为稳态时 90%的母亲需要超过的阈值，以确保胎儿下丘脑-垂体-肾上腺轴抑制。
开发了一个两室地塞米松药代动力学模型，并对其进行了评估，结果表明该模型适合于目的。包括对假定胎儿：母体地塞米松浓度比的敏感性分析在内的模拟结果表明，7.5μg/kg/天是最小有效剂量，也是我们建议的剂量。
我们得出结论，传统的地塞米松剂量是所需剂量的三倍，可能会对治疗中的胎儿和母亲造成伤害。应在前瞻性临床试验中检验我们推荐剂量的临床相关性和适当性。
