Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146, Hamburg, Germany.
Research DMPK, Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
J Pharmacokinet Pharmacodyn. 2022 Apr;49(2):135-149. doi: 10.1007/s10928-021-09780-x. Epub 2021 Sep 28.
Determining and understanding the target-site exposure in clinical studies remains challenging. This is especially true for oral drug inhalation for local treatment, where the target-site is identical to the site of drug absorption, i.e., the lungs. Modeling and simulation based on clinical pharmacokinetic (PK) data may be a valid approach to infer the pulmonary fate of orally inhaled drugs, even without local measurements. In this work, a simulation-estimation study was systematically applied to investigate five published model structures for pulmonary drug absorption. First, these models were compared for structural identifiability and how choosing an inadequate model impacts the inference on pulmonary exposure. Second, in the context of the population approach both sequential and simultaneous parameter estimation methods after intravenous administration and oral inhalation were evaluated with typically applied models. With an adequate model structure and a well-characterized systemic PK after intravenous dosing, the error in inferring pulmonary exposure and retention times was less than twofold in the majority of evaluations. Whether a sequential or simultaneous parameter estimation was applied did not affect the inferred pulmonary PK to a relevant degree. One scenario in the population PK analysis demonstrated biased pulmonary exposure metrics caused by inadequate estimation of systemic PK parameters. Overall, it was demonstrated that empirical modeling of intravenous and inhalation PK datasets provided robust estimates regarding accuracy and bias for the pulmonary exposure and pulmonary retention, even in presence of the high variability after drug inhalation.
在临床研究中确定和了解目标部位暴露仍然具有挑战性。对于局部治疗的口服药物吸入尤其如此，因为目标部位与药物吸收部位相同，即肺部。基于临床药代动力学 (PK) 数据的建模和模拟可能是推断口服吸入药物肺部命运的有效方法，即使没有局部测量也是如此。在这项工作中，系统地应用了模拟-估计研究来调查用于肺部药物吸收的五个已发表的模型结构。首先，比较了这些模型的结构可识别性，以及选择不合适的模型如何影响对肺部暴露的推断。其次，在群体方法的背景下，评估了静脉给药和口服吸入后顺序和同时参数估计方法通常应用的模型。对于具有适当模型结构和静脉注射后特征良好的系统 PK 的情况，在大多数评估中，推断肺部暴露和保留时间的误差不到两倍。无论是应用顺序还是同时参数估计，都不会在相关程度上影响推断的肺部 PK。群体 PK 分析中的一个方案表明，由于对系统 PK 参数的估计不足，导致肺部暴露指标存在偏差。总体而言，即使在药物吸入后存在高度变异性的情况下，静脉注射和吸入 PK 数据集的经验模型也证明了对肺部暴露和肺部保留的准确性和偏差具有稳健的估计。
