Toulitsis Elias, Tsekouras Athanasios A, Macheras Panos
Faculty of Pharmacy, National and Kapodistrian University of Athens, 15784 Athens, Greece.
Department of Chemistry, National and Kapodistrian University of Athens, 15784 Athens, Greece.
Pharmaceutics. 2024 Nov 11;16(11):1435. doi: 10.3390/pharmaceutics16111435.
It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug's gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time (F.A.T.) concept and the relevant physiologically based finite-time pharmacokinetic (PBFTPK) models developed provided a better physiologically sound description of oral drug absorption. In this study, we re-analyzed, using PBFTPK models, seven data sets of ketoprofen, amplodipine, theophylline (three formulations), and two formulations (reference, test) from a levonorgestrel bioequivalence study. Equations for one-compartment-model drugs, for the estimation of fraction of dose absorbed or the bioavailable fraction exclusively from oral data, were developed. In all cases, meaningful estimates for (i) the number of absorption stages, namely, one for ketoprofen and the levonorgestrel formulations, two for amlodipine, the immediate-release theophylline formulation, and the extended-release Theotrim formulation, and three for the extended-release Theodur formulation, (ii) the duration of each absorption stage and the corresponding drug input rate, and (iii) the total duration of drug absorption, which ranged from 0.75 h (ketoprofen) to 11.6 h for Theodur were derived. Estimates for the bioavailable fraction of ketoprofen and two theophylline formulations exhibiting one-compartment-model kinetics were derived. This study provides insights into the detailed characteristics of oral drug absorption. The use of PBFTPK models in drug absorption analysis can be leveraged as a computational framework to discontinue the perpetuation of the mathematical fallacy of classical pharmacokinetic analysis based on the absorption rate constant as well as in the physiologically based pharmacokinetic (PBPK) studies and pharmacometrics. The present study is an additional piece of evidence for the scientific and regulatory changes required to be implemented by the regulatory agencies in the not-too-distant future.
业已证明，与驱动药物胃肠道吸收速率的吸收速率常数相关的无限吸收时间概念在生理学上是不合理的。最近基于有限吸收时间（F.A.T.）概念对口服药物吸收数据进行的分析以及所开发的相关生理基础有限时间药代动力学（PBFTPK）模型，为口服药物吸收提供了更好的生理学合理描述。在本研究中，我们使用PBFTPK模型重新分析了酮洛芬、氨氯地平、茶碱（三种制剂）以及左炔诺孕酮生物等效性研究中的两种制剂（参比制剂、受试制剂）的七个数据集。开发了用于单室模型药物的方程，以仅根据口服数据估算吸收剂量分数或生物利用度分数。在所有情况下，均得出了有意义的估算值，包括：（i）吸收阶段的数量，即酮洛芬和左炔诺孕酮制剂为1个，氨氯地平、速释茶碱制剂和缓释茶喘平制剂为2个，缓释TheoDur制剂为3个；（ii）每个吸收阶段的持续时间及相应的药物输入速率；（iii）药物吸收的总持续时间，范围从酮洛芬的0.75小时到TheoDur的11.6小时。得出了表现出单室模型动力学的酮洛芬和两种茶碱制剂的生物利用度分数估算值。本研究深入了解了口服药物吸收的详细特征。在药物吸收分析中使用PBFTPK模型可作为一种计算框架，以终止基于吸收速率常数的经典药代动力学分析在数学上的谬误，以及在生理基础药代动力学（PBPK）研究和药物计量学中的延续。本研究为监管机构在不久的将来需要实施的科学和监管变革提供了又一证据。
