Comin Léa, Marie Solène, Ursino Moreno, Zohar Sarah, Tournier Nicolas, Comets Emmanuelle
Inserm, UMRS 1346, Université Paris Cité, Inria, HeKA, 75015, Paris, France.
Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Université Paris-Saclay, Service Hospitalier Frédéric Joliot, Orsay, France.
Clin Pharmacokinet. 2025 Sep 17. doi: 10.1007/s40262-025-01562-9.
Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacokinetic studies based on blood sampling. Here, we build a pharmacokinetic (PK) model from WB4D PET data obtained using a microdose of radiolabeled glyburide ([C]glyburide) in humans, aiming to describe the biodistribution of this drug and compare estimated pharmacokinetic parameters with the parameters obtained in standard PK studies.
The present work analyzes data acquired over 40 min after injection of [C]glyburide in 16 healthy subjects using non-linear mixed-effect models (NLMEM). In 10 subjects, a second PET acquisition was performed after rifampicin administration, which may cause a drug-drug interaction and inhibit the liver uptake transport of glyburide. Arterial blood, liver, kidneys, pancreas, and spleen kinetics were modeled using NLMEM. The model-building strategy involved selecting the structural model using baseline [C]glyburide PET data and then selecting the covariate model (rifampicin, age, and gender) and refining the structure of the interindividual variability model using both administration periods. Model selection was based on the corrected Bayesian information criterion and implemented in Monolix software.
The final model included seven compartments, with two compartments each for the Liver and kidneys to account for within-tissue exchanges. Rifampicin decreased the Liver distribution by 261%.
The estimated central volume of distribution (V = 3.6 L) and elimination rate (k = 0.8 h) were consistent with the known pharmacokinetics of glyburide, which is a promising first step in leveraging microdose data to study the WB4D biodistribution.
EudraCT identifier no. 2017-001703-69.
使用药物放射性标记类似物的全身动态（WB4D）正电子发射断层扫描（PET）成像数据大多采用描述性方法进行分析，与基于血样采集的传统药代动力学研究无关。在此，我们利用人体微量放射性标记格列本脲（[C]格列本脲）获得的WB4D PET数据构建药代动力学（PK）模型，旨在描述该药物的生物分布，并将估计的药代动力学参数与标准PK研究中获得的参数进行比较。
本研究使用非线性混合效应模型（NLMEM）分析了16名健康受试者注射[C]格列本脲后40分钟内获取的数据。在10名受试者中，服用利福平后进行了第二次PET采集，利福平可能会引起药物相互作用并抑制格列本脲的肝脏摄取转运。使用NLMEM对动脉血、肝脏、肾脏、胰腺和脾脏的动力学进行建模。模型构建策略包括使用基线[C]格列本脲PET数据选择结构模型，然后选择协变量模型（利福平、年龄和性别），并使用两个给药期完善个体间变异性模型的结构。模型选择基于校正的贝叶斯信息准则，并在Monolix软件中实施。
最终模型包括七个隔室，肝脏和肾脏各有两个隔室以考虑组织内交换。利福平使肝脏分布减少了261%。
估计的中央分布容积（V = 3.6 L）和消除率（k = 0.8 h）与格列本脲已知的药代动力学一致，这是利用微量数据研究WB4D生物分布的有希望的第一步。
欧盟临床试验数据库标识符：2017-001703-69。
