## 3 Prediction of Human Pharmacokinetics  
_In silico_ ADME-PK (absorption, distribution, metabolism, excretion, and pharmacokinetics) is the use of computer modeling to understand structure-property relationships and to predict DMPK (drug metabolism and pharmacokinetics) properties from compound structure. This is related to but distinct from physiologically based pharmacokinetic (PBFK) modeling, which strives to provide accurate predictions of the PK profile of drug candidates [46]. The focus of _in silico_ ADME-PK is to guide the design of novel compounds with superior ADME properties. Most often a quantitative structure-property relationship (QSPR) approach is used to relate a compound's structure to the chemical property in question (e.g., cell permeability or metabolic clearance) measured in an _in vitro_ assay. Related terms are also quantitative-structure-activity relationships (QSAR), when a set of predictor variables is related to the potency of the drug. Orally administered products are subject to a sequence of transport and enzymatic barriers in enterohepatic systems affecting bioavailability, including extraction in the intestinal and liver tissues, which could impact the fraction of the orally administered dose that reaches the systemic circulation and thereby the site of action. Bioavailability is mainly dependent on three general and rather complex serial processes: the fraction of the oral dose that is absorbed (F\({}_{\text{abs}}\)), the first-pass extraction of the drug in the gut wall (E\({}_{\text{G}}\)), and the first-pass extraction of the drug in the liver (E\({}_{\text{H}}\)) [47]. In general, oral products with a low F (<25%-35%) have a higher inter- and intra-individual variability in plasma exposure (coefficient of variation >60%-120%) [48]. Drugs with high degree of F\({}_{\text{abs}}\) show sufficiently high solubility of the active pharmaceutical ingredient (API), no luminal degradation, and absorption along the small and/or large intestine [49; 50]. The regulatory framework Biopharmaceutics Classification System (BCS) of drugs provides information relevant to understanding and predicting GI drug absorption and bioavailability in general, which is relevant to the absorption potential in the small and large intestine [51]. After the drug is absorbed, it passes to the liver, which expresses a broader range of different enzymes compared to the intestine [52], such as the family of CYP enzymes [53]. Other enzymes such as microsomal uridine 5'-diphospho-glucuronosyltransferase (UGTs), sulfotransferases, and glutathione S-transferases are found in great amounts in the human liver [54]. Humans show large inter-individual variation in the amount of different enzymes, which accounts, in part, for the large inter-individual variation reported for E\({}_{\text{H}}\) and CL. A considerable large inter-individual variation in the expression of the different CYP isoforms has also been observed, ranging from 20-(CYP2E1 and CYP3A4) to \(>\)1000-fold (CYP2D6). The liver is also the major organ for glucuronidation in the body. Glucuronide conjugates have molecular characteristics that are associated with biliary excretion of a compound, i.e., a high molecular weight, ionized and the presence of polar groups [55]. The identification and quantification of the important PK processes described above can be investigated in relevant _in vitro_ models, and predictions of PK properties like regional intestinal permeability can be made early [56]. Most importantly, an estimate of human drug clearance will determine how fast a drug is eliminated, and conversely define the dose range to study in FIH [57]. Several different models have been suggested for the prediction of oral absorption for the biopharmaceutical design of oral drug delivery systems [58; 59]. The proposed BDDCS has been shown to be useful in predicting some crucial ADME parameters and especially the transport/absorption/elimination interplay [60].