Animal models are frequently used to aid prediction of intestinal absorption in humans. However, there is little comparative quantitative information on species differences in paracellular permeation, which is an important route for oral absorption of small to medium-sized hydrophilic drug molecules. This study addresses this issue by comparing the molecular mass (MM) dependency in oral bioavailability between rat and dog of poly(ethylene glycol) (PEG), a polydispersed model mixture commonly used to characterize paracellular absorption, and of a series of eight D-peptides (based on D-phenylalanine). Fasted rats and dogs received PEG (400/900) and the D-peptides (MM 236-406 Da), orally and intravenously, with total 24-48 h urine collection to estimate oral bioavailability. After HPLC separation, the individual PEG oligomers and D-peptides were determined using radiometric detection, for radiolabeled material, and LC-MS, for unlabeled (PEG) material. All compounds were predominantly excreted unchanged following intravenous administration. After oral administration, the predominant peak in the radiochromatogram was unchanged material, indicating stability of the compounds in the gastrointestinal tract. A clear molecular mass dependency in oral bioavailability was seen with both series, but with absorption much greater in dog than rat. Thus, for PEG in rat, bioavailability decreased sharply from 79 to around 2% with increasing MM between 282 and 591 Da, and then tapered to around 1. 5% up to 1295 Da. Whereas in dog, bioavailability remained around 100% for oligomers up to 600 Da and then decreased quite sharply with increasing MM, tending to plateau around 13% beyond 900 Da. Likewise, for the d-peptides in rat, bioavailability decreased from 30 to 1% with increasing MM between 236 and 406 Da, whereas in dog it was 100%, declining to 16% over the same molecular range. This species difference appears to be due to a larger pore size and greater frequency of pores in the paracellular pathway of dog compared to rat. Furthermore, on the basis of comparison with literature data for PEG and selected drugs, rat would appear to be a better predictor than dog of absorption of hydrophilic compounds in human.

We assess the advancement of physiologically based pharmacokinetic (PBPK) modeling and simulation (M&S) over the last 20 years (start of 2000 to end of 2019) focusing on the trends in each decade with the relative contributions from different organizations, areas of applications, and software tools used. Unlike many of the previous publications which focused on regulatory applications, our analysis is based on PBPK publications in peer‐reviewed journals based on a large sample (>700 original articles). We estimated a rate of growth for PBPK (>40 fold/20 years) that was much steeper than the general pharmacokinetic modeling (<3 fold/20 years) or overall scientific publications (∼3 fold/20 years). The analyses demonstrated that contrary to commonly held belief, commercial specialized PBPK platforms with graphical‐user interface were a much more popular choice than open‐source alternatives even within academic organizations. These platforms constituted 81% of the whole set of the sample we assessed. The major PBPK applications (top 3) were associated with the study design, predicting formulation effects, and metabolic drug–drug interactions, while studying the fate of drugs in special populations, predicting kinetics in early drug development, and investigating transporter drug interactions have increased proportionally over the last decade. The proportions of application areas based on published research were distinctively different from those shown previously for the regulatory submissions and impact on labels. This may demonstrate the lag time between the research applications versus verified usage within the regulatory framework. The report showed the trend of overall PBPK publications in pharmacology drug development from the past 2 decades stratified by the organizations involved, software used, and area of applications. The analysis showed a more rapid increase in PBPK than that of the pharmacokinetic space itself with an equal contribution from academia and industry. By establishing and recording the journey of PBPK modeling in the past and looking at its current status, the analysis can be used for devising plans based on the anticipated trajectory of future regulatory applications.

Three methods for estimation of the equilibrium tissue-to-plasma partition ratios (Kp values) in the presence of tissue concentration time data have been investigated. These are the area method, the open loop (tissue specific) method and the whole body model(closed loop) method, each with different model assumptions. Additionally, multiple imputations, a technique for dealing with deficiencies in data sets (i.e., missing tissues) is used. The estimated Kp values by the three methods have been compared and the limitations and advantages of each approach drawn. The area method, which is essentially model free, gives only a crude estimate of Kp without making any statement of its uncertainty; whereas both the open and closed loop methods provide an estimate of this. The closed loop method, where the most assumptions are made, is the approach that gives the best overall estimates of Kp, which was confirmed by comparing the predicted concentration-time profiles with experimental data. Although the estimates from the closed loop method, as well as the other two methods, are conditioned on the data, they are the most reliable for both propagating parameter variability and uncertainty through a whole body physiologically based model, as well as for extrapolation to human. A series of benzodiazepines, namely alprazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, midazolam and triazolam in rat is used as a case study in the current investigation.

This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.

PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.