Alsmadi Mo'tasem M
Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; and.
Nanotechnology Institute, Jordan University of Science and Technology, Irbid, Jordan.
Ther Drug Monit. 2024 Aug 1;46(4):512-521. doi: 10.1097/FTD.0000000000001172. Epub 2024 Feb 16.
Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC 50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling.
An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses.
After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL.
Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC 50 for newborns must be confirmed.
孕期阿片类药物使用障碍（OUD）与高死亡率及新生儿阿片类药物戒断综合征（NOWS）相关。阿片类药物丁丙诺啡用于治疗OUD和NOWS。丁丙诺啡的活性代谢物（去甲丁丙诺啡）可穿过胎盘，在高脑细胞外液（bECF）水平时导致新生儿呼吸抑制（半数有效浓度[EC50]=35纳克/毫升）。使用唾液进行新生儿治疗药物监测可降低因频繁采血带来的不适和感染风险。
构建了一个基于生理药代动力学的成人模型，用于模拟静脉注射和舌下给药后丁丙诺啡和去甲丁丙诺啡的药代动力学过程，并对其进行了验证和尺度转换，以适用于新生儿和孕妇群体。妊娠模型预测丁丙诺啡和去甲丁丙诺啡剂量会经胎盘转移至新生儿体内。基于生理药代动力学的新生儿模型用于估计这些剂量后新生儿血浆、bECF和唾液中丁丙诺啡和去甲丁丙诺啡的水平。
母亲舌下给予丁丙诺啡（4毫克/天）后，新生儿中丁丙诺啡和去甲丁丙诺啡的估计血浆浓度分别在8小时和24小时内超过毒性阈值。然而，去甲丁丙诺啡的bECF水平低于呼吸抑制阈值。此外，观察到新生儿中丁丙诺啡镇痛、去甲丁丙诺啡镇痛和去甲丁丙诺啡通气不足的唾液丁丙诺啡阈值水平分别为22、2和162纳克/毫升。
使用新生儿唾液进行丁丙诺啡治疗药物监测有助于在母亲使用舌下丁丙诺啡治疗OUD期间保障新生儿安全。然而，必须确认将成人呼吸抑制EC50值用于新生儿的适用性。
