University of Pittsburgh, Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA.
Indivior Solutions, Inc.
Br J Clin Pharmacol. 2018 Sep;84(9):2075-2087. doi: 10.1111/bcp.13642. Epub 2018 Jun 21.
Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy.
A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study.
The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2 and 3 trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3 trimester (-26.3%).
PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.
丁丙诺啡（BUP）经美国食品和药物管理局批准用于治疗阿片类药物成瘾。目前，孕妇使用 BUP 的剂量方案是基于为非孕妇设计的建议。然而，怀孕期间的生理变化可能会改变 BUP 的暴露和疗效。本研究的目的是为孕妇建立丁丙诺啡的基于生理的药代动力学（PBPK）模型，预测不同妊娠阶段 BUP 暴露的变化，并展示 PBPK 模型在优化孕妇 BUP 药物治疗中的效用。
最初在健康受试者中建立并验证了丁丙诺啡的完整 PBPK 模型。该模型中包含了胎儿胎盘隔室，以模拟妊娠引起的解剖和生理变化。此外，还将生理参数的妊娠变化纳入该模型。将 PBPK 模型预测的孕妇和产后 BUP 暴露与前瞻性临床研究的已发表数据进行了比较。
虚拟孕妇人群中 BUP 血浆浓度-时间曲线的预测值与 2 至 3 个妊娠期和产后的观察数据一致。在 12 小时内，剂量归一化的 AUC0-12、平均浓度和最大浓度的预测均值与观察均值的差异在±25%以内，除了 3 个妊娠期的平均浓度（-26.3%）。
基于 PBPK 模型的模拟可能是优化孕妇 BUP 药物治疗的有用工具，避免了在每个妊娠期和产后进行通常需要密集采血的药代动力学研究的需要。
