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.

中文翻译：

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妊娠期间倍他米松和地塞米松给药方案的优化：基于胎盘灌注和妊娠生理学的联合药代动力学建模方法


产前倍他米松和地塞米松用于早产高风险的女性，以预防新生儿呼吸窘迫综合征（RDS）。目前的治疗方案虽然能有效预防新生儿 RDS，但可能并不理想。最近，人们担心胎儿药物暴露量高可能导致长期不良神经后果。来自非人类灵长类动物和绵羊的数据表明，将胎儿血浆浓度维持在 1 ng/mL 以上 48 小时以保持疗效，同时避免出现不良的胎儿血浆浓度。我们的目的是重新评估当前的倍他米松和地塞米松剂量策略，以评估估计的胎儿暴露量，并提供满足功效目标但避免峰值暴露过多的新剂量建议。基于妊娠生理学的药代动力学（PBPK）模型用于预测胎儿药物暴露。为了预测胎儿中倍他米松和地塞米松的暴露程度，进行胎盘灌注实验以确定胎盘转移。将胎盘转移率整合到 PBPK 模型中以预测胎儿暴露，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 模型来模拟替代给药方案，以建立模型知情的剂量。离体数据显示，这两种药物都能广泛穿过胎盘。对于倍他米松 15.7±1.7% 和地塞米松 14.4±1.5%，初始母体灌注液浓度在 3 小时灌注期结束时达到胎儿循环。包含这些离体胎盘转移率的妊娠 PBPK 模型可以准确预测当前给药方案导致的母体和胎儿暴露情况。 剂量模拟表明，对于肌注倍他米松，剂量从 2 个剂量 11.4 mg（间隔 24 小时）减少到 4 个剂量 1.425 mg（间隔 12 小时）可以避免过多的峰值暴露，并且仍然满足胎儿反应阈值。对于地塞米松，剂量可以从每 12 小时 4 次 6 毫克减少到每 6 小时 8 次 1.5 毫克。胎盘灌注和妊娠 PBPK 联合建模方法充分预测了母体和胎儿 2 种产前皮质类固醇 (ACS) 的药物暴露。引人注目的是，我们的 PBPK 模拟表明，药物剂量可能会大幅减少，以仍然满足先前提出的功效目标并最大限度地减少峰值暴露。我们建议使用所提供的模型知情给药方案来支持对更新的 ACS 方案和临床试验设计的进一步讨论，以确认较低剂量的有效性和安全性。