School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia.
Eur J Clin Pharmacol. 2011 Sep;67(9):899-908. doi: 10.1007/s00228-011-1023-6. Epub 2011 Mar 11.
The aim of this investigation was to demonstrate that nonlinear mixed-effects population pharmacokinetic (PK) modeling can be used to evaluate data from studies of drug transport/excretion into human milk and hence to estimate infant exposure.
A sparse dataset from a previously published study of the use of oral tramadol for post-cesarean pain management in 75 lactating women was used. Milk and plasma samples were collected during days 2-4 of lactation, and tramadol and O-desmethyltramadol (ODT) concentration measurements in these samples were available. Absolute infant dose was obtained from the concentration measurements and estimated milk volume ingested, and expressed in micrograms per kilogram per day. Relative infant dose was calculated as a percentage of the absolute infant dose divided by the maternal dose (μg/kg/day). Nonlinear mixed-effects modeling was used to fit a population PK model to the data.
The disposition of tramadol and ODT in plasma and the transition of these substances into milk were characterized by a five-compartment population PK mixture model with first-order absorption. The polymorphic ODT formation clearance in the plasma compartment was able to be characterized in both CYP2D6-poor and -extensive metabolizers. Milk creamatocrit was a significant covariate in ODT transfer between the plasma and milk compartments. The estimated relative infant doses in extensive and poor metabolizers, respectively, were 2.16 ± 0.57 and 2.60 ± 0.57% for tramadol, and 0.93 ± .20 and 0.47 ± 0.10% for ODT.
This study demonstrates that a population PK approach with sparse sampling of analytes in milk and plasma can yield quality information about the transfer process and that it also can be used to estimate the extent of infant exposure to maternal drugs via milk.
本研究旨在证明非线性混合效应群体药代动力学（PK）模型可用于评估药物向人乳中转运/排泄的研究数据，从而估算婴儿的暴露情况。
使用先前发表的一项研究中的稀疏数据集，该研究评估了 75 例哺乳期妇女使用口服曲马多治疗剖宫产术后疼痛的情况。在哺乳期的第 2-4 天采集乳汁和血浆样本，并可获得这些样本中曲马多和 O-去甲基曲马多（ODT）的浓度测量值。通过浓度测量值和估计的摄入乳汁量获得婴儿的绝对剂量，并以微克/千克/天表示。相对婴儿剂量通过将绝对婴儿剂量除以母体剂量（μg/kg/天）计算得出。采用非线性混合效应模型对数据进行群体 PK 模型拟合。
曲马多和 ODT 在血浆中的处置以及这些物质向乳汁中的转移，通过一个具有一级吸收的五室群体 PK 混合模型来描述。在血浆中具有多态性的 ODT 形成清除率，可在 CYP2D6 弱代谢者和广泛代谢者中进行描述。在 ODT 从血浆向乳汁转移的过程中，乳汁乳糜比是一个显著的协变量。广泛代谢者和弱代谢者的婴儿相对剂量分别为曲马多的 2.16±0.57%和 2.60±0.57%，ODT 的 0.93±0.20%和 0.47±0.10%。
本研究表明，采用乳汁和血浆中分析物稀疏采样的群体 PK 方法可以提供有关转移过程的高质量信息，并且还可以用于估计婴儿通过乳汁暴露于母体药物的程度。
