Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Pediatrics, Duke University Medical Center, Durham.
Ther Drug Monit. 2019 Dec;41(6):761-765. doi: 10.1097/FTD.0000000000000670.
Solithromycin is a fourth-generation macrolide antibiotic with potential efficacy in pediatric community-acquired bacterial pneumonia. Pharmacokinetic (PK) studies of solithromycin in pediatric subjects are limited, therefore application of minimally invasive drug sampling techniques, such as dried blood spots (DBS), may enhance the enrollment of children in PK studies. The objectives of this study were to compare solithromycin concentrations in DBS with those in liquid plasma samples (LPS) and to quantify the effects of modeling DBS concentrations on the results of a population PK model.
Comparability analysis was performed on matched DBS and LPS solithromycin concentrations collected from two different phase 1 clinical trials of solithromycin treatment in children (clinicaltrials.gov #NCT01966055 and #NCT02268279). Comparability of solithromycin concentrations was evaluated based on DBS:LPS ratio, median percentage prediction error, and median absolute percentage prediction error. The effect of correcting DBS concentrations for both hematocrit and protein binding was investigated. In addition, a previously published population PK model (NONMEM) was leveraged to compare parameter estimates resulting from either DBS or LPS concentrations.
A total of 672 paired DBS-LPS concentrations were available from 95 subjects (age: 0-17 years of age). The median (range) LPS and DBS solithromycin concentrations were 0.3 (0.01-12) mcg/mL and 0.32 (0.01-14) mcg/mL, respectively. Median percentage prediction error and median absolute percentage prediction error of raw DBS to LPS solithromycin concentrations were 5.26% and 22.95%, respectively. In addition, the majority of population PK parameter estimates resulting from modeling DBS concentrations were within 15% of those obtained from modeling LPS concentrations.
Solithromycin concentrations in DBS were similar to those measured in LPS and did not require correction for hematocrit or protein binding.
索利霉素是一种第四代大环内酯类抗生素，在儿科社区获得性细菌性肺炎中有潜在疗效。索利霉素在儿科患者中的药代动力学（PK）研究有限，因此应用微创药物采样技术，如干血斑（DBS），可能会增加 PK 研究中儿童的入组率。本研究的目的是比较 DBS 与液体血浆样本（LPS）中索利霉素的浓度，并定量评估建模 DBS 浓度对群体 PK 模型结果的影响。
对来自两项不同的索利霉素治疗儿童的 I 期临床试验（clinicaltrials.gov #NCT01966055 和 #NCT02268279）中收集的匹配 DBS 和 LPS 索利霉素浓度进行可比性分析。根据 DBS：LPS 比值、中位数预测误差百分比和中位数绝对预测误差百分比评估索利霉素浓度的可比性。考察了校正 DBS 浓度的红细胞压积和蛋白结合的效果。此外，还利用之前发表的群体 PK 模型（NONMEM）比较了来自 DBS 或 LPS 浓度的参数估计值。
共有 95 名受试者（年龄：0-17 岁）的 672 对 DBS-LPS 浓度可供使用。LPS 和 DBS 索利霉素的中位数（范围）浓度分别为 0.3（0.01-12）mcg/mL 和 0.32（0.01-14）mcg/mL。DBS 与 LPS 索利霉素浓度的原始 DBS 中位数预测误差和中位数绝对预测误差百分比分别为 5.26%和 22.95%。此外，来自建模 DBS 浓度的大多数群体 PK 参数估计值都在从建模 LPS 浓度获得的参数估计值的 15%以内。
DBS 中的索利霉素浓度与 LPS 测量的浓度相似，且不需要校正红细胞压积或蛋白结合。
