Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
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DOI：
10.1007/s10928-015-9438-9
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发表时间：
2015-12-01
影响因子：
2.5
通讯作者：
Simonsson, Ulrika S. H.
中科院分区：
文献类型：
--
作者：
Clewe, Oskar;Karlsson, Mats O.;Simonsson, Ulrika S. H.
支气管肺泡灌洗(BAL)是一种肺部采样技术，用于表征上皮衬里液体和肺泡细胞中的药物浓度。两种假想药物具有不同的肺分布速率(快和慢)。一个优化的BAL抽样设计是在假设之前没有关于肺部分布(比率和范围)的信息的情况下产生的，每个受试者最多有两个样本。进行模拟以评估每个受试者的样本数量(1或2)和样本大小对参数估计(肺分布的速率和范围)的相对偏差和相对均方误差的影响。优化的BAL采样设计依赖于特征的血药浓度时间分布、群体血浆药代动力学模型、BAL方法的定量极限(LOQ)，并且只涉及两个BAL采样时间点，一个提前，一个延迟。早期样本应该尽可能早地采集，因为BAL液中的浓度为千分之一日元LOQ。第二次采样应在血浆曲线下降部分的时间点进行，在该时间点上，血浆浓度与早期样品中的血浆浓度相当。使用先前描述的与血浆群体药代动力学模型相关联的一般肺分布模型，使用最终的BAL抽样设计的模拟数据能够表征肺分布的速率和范围。优化的BAL抽样设计能够表征快速和缓慢平衡药物的肺部分布的速度和范围。
Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid a parts per thousand yen LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.