Abstract
Oral administration is the preferred and predominant route of choice for medication. As such, drug absorption is one of critical drug metabolism and pharmacokinetics (DM/PK) parameters that should be taken into consideration in the process of drug discovery and development. The cell-free in vitro parallel artificial membrane permeability assay (PAMPA) has been adopted as the primary screening to assess the passive diffusion of compounds in the practical applications. A classical quantitative structure–activity relationship (QSAR) model and a machine learning (ML)-based QSAR model were derived using the partial least square (PLS) scheme and hierarchical support vector regression (HSVR) scheme to elucidate the underlying passive diffusion mechanism and to predict the PAMPA effective permeability, respectively, in this study. It was observed that HSVR executed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical assessments. When applied to the mock test, which was designated to mimic real challenges, HSVR also showed better predictive performance. PLS, conversely, cannot cover some mechanistically interpretable relationships between descriptors and permeability. Accordingly, the synergy of predictive HSVR and interpretable PLS models can be greatly useful in facilitating drug discovery and development by predicting passive diffusion.
Highlights
The oral route is the simplest and most convenient means for administrating drugs [1]
Both log P and log D were included in this study (Table 1) and partial least square (PLS) derived in this investigation gave positive coefficients to both descriptors (Equation (1)) suggesting that parallel artificial membrane permeability assay (PAMPA) permeability increases with both descriptors that is consistent with most of published models
PAMPA is often used as a surrogate for preliminary assessment of drug absorption, which plays a critical role in drug bioavailability
Summary
The oral route is the simplest and most convenient means for administrating drugs [1]. Oral administration is the most prevalent route of drug administration that can be manifested by Figure 1, which displays the administration routes and the corresponding ratios for 629 unique compounds approved by US FDA in 2018 based on the analysis of FDA data Absorption is one of critical factors in absorption, distribution, metabolism and excretion, and toxicity (ADME/Tox) profiling in the process of drug discovery and development [2]. Poor absorption can make a partial contribution to clinical failures [3]. Its practical applications have been severely hampered by its poor absorption [5,6]
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