An Investigation into the Factors Governing Drug Absorption and Food Effect Prediction Based on Data Mining Methodology.

Drug absorption is a complex process governed by a number of interrelated physicochemical, biopharmaceutical, and pharmacokinetic factors. In order to explore complex relationships among these factors, multivariate exploratory analysis was performed on the dataset of drugs with diverse bioperformance. The investigated dataset included subset of drugs for which bioequivalence between solid dosage form and oral solution has been reported, and subset of drugs described in the literature as low solubility/low permeability compounds. Discriminatory power of hierarchical clustering on principal components was somewhat higher when applied on the data subsets of drugs with similar bioperformance, while analysis of the integrated dataset indicated existence of two groups of drugs with the boundaries reflected in Peff value of approximately 2 × 10-4 cm/s and Fa and Fm values higher than 85% and 50%, respectively. Majority of the investigated drugs within the integrated dataset were grouped within their initial subset indicating that overall drug bioperformance is closely related to its physicochemical, biopharmaceutical and pharmacokinetic properties. Classification models constructed using the random forest (RF) and support vector machine with polynomial kernel function were able to predict food effect based on drug dose/solubility ratio (D/S), effective permeability (Peff), percent of dose metabolized (Fm), and elimination half-life (τ1/2). Although both models performed well during training and testing, only RF kept satisfying performance when applied on the external dataset (kappa value > 0.4). The results obtained indicate that data mining can be employed as useful tool in biopharmaceutical drug characterization which merits further investigation.