Van Der Heijden Joyce E M, Van Hove Hedwig, Van Elst Niki M, Van Den Broek Petra, Van Drongelen Joris, Scheepers Hubertina C J, De Wildt Saskia N, Greupink Rick
Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Am J Obstet Gynecol. 2025 Feb;232(2):228.e1-228.e9. doi: 10.1016/j.ajog.2024.05.012. Epub 2024 May 17.
Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome (RDS). The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from nonhuman primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels.
We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures.
A pregnancy physiologically based pharmacokinetic (PBPK) model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal pharmacokinetic data. The verified pregnancy PBPK models were then used to simulate alternative dosing regimens to establish a model-informed dose.
Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7±1.7% and for dexamethasone 14.4±1.5%, the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy PBPK models that include these ex vivo-derived placental transfer rates accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular, a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from 4 times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours.
A combined placenta perfusion and pregnancy PBPK modeling approach adequately predicted both maternal and fetal drug exposures of 2 antenatal corticosteroids (ACSs). Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated ACS scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.
对于有早产高风险的孕妇，会使用产前倍他米松和地塞米松来预防新生儿呼吸窘迫综合征（RDS）。目前的治疗方案虽能有效预防新生儿RDS，但可能并非最优。最近，人们对因胎儿药物暴露量高而可能产生的长期不良神经学后果表示担忧。来自非人灵长类动物和绵羊的数据表明，为保持疗效，需使胎儿血浆浓度在48小时内维持在1 ng/mL以上，同时避免胎儿血浆水平过高。
我们旨在重新评估当前倍他米松和地塞米松的给药策略，以评估估计的胎儿暴露量，并提供既能达到疗效目标又能避免过高峰值暴露的新给药方案。
使用基于妊娠生理的药代动力学（PBPK）模型来预测胎儿药物暴露量。为预测倍他米松和地塞米松在胎儿体内的暴露程度，进行了胎盘灌注实验以确定胎盘转运情况。将胎盘转运率整合到PBPK模型中以预测胎儿暴露量，并使用已发表的母体和胎儿药代动力学数据验证模型性能。然后使用经过验证的妊娠PBPK模型模拟替代给药方案，以确定基于模型的剂量。
体外数据表明，两种药物都能大量穿过胎盘。对于倍他米松，在3小时灌注期结束时，初始母体灌注液浓度的15.7±1.7%进入胎儿循环；对于地塞米松，这一比例为14.4±1.5%。包含这些体外获得的胎盘转运率的妊娠PBPK模型准确预测了当前给药方案导致的母体和胎儿暴露量。剂量模拟表明，对于肌肉注射倍他米松，剂量可从间隔24小时的2次11.4 mg减至间隔12小时的4次1.425 mg，这样既能避免过高的峰值暴露，又能达到胎儿反应阈值。对于地塞米松，剂量可从每12小时4次6 mg减至每6小时8次1.5 mg。
胎盘灌注与妊娠PBPK建模相结合的方法能够充分预测两种产前皮质类固醇（ACSs）的母体和胎儿药物暴露量。引人注目的是，我们的PBPK模拟表明，药物剂量可能大幅降低，仍能达到先前提出的疗效目标，并将峰值暴露降至最低。我们建议使用所提供的基于模型的给药方案，以支持就更新的ACS方案进行进一步讨论，并设计临床试验来确认较低剂量的有效性和安全性。
