In 2005, a survey compared a number of commercial PBPK software available at the time, mainly focusing on 'ready to use' modelling tools. Since then, these tools and software have been further developed and improved to allow modellers to perform WB-PBPK modelling including ADME processes at a high level of sophistication. This review presents a comparison of the features, values and limitations of both the 'ready to use' software and of the traditional user customizable software that are frequently used for the building and use of PBPK models, as well as the challenges associated with the various modelling approaches regarding their current and future use. PBPK models continue to be used more and more frequently during the drug development process since they represent a quantitative, physiologically realistic platform with which to simulate and predict the impact of various potential scenarios on the pharmacokinetics and pharmacodynamics of drugs. The 'ready to use' PBPK software has been a major factor in the increasing use of PBPK modelling in the pharmaceutical industry, opening up the PBPK approach to a broader range of users. The challenge is now to educate and to train scientists and modellers to ensure their appropriate understanding of the assumptions and the limitations linked both to the physiological framework of the 'virtual body' and to the scaling methodology from in vitro to in vivo (IVIVE).

Individual adjustment of oral etoposide based on unbound pharmacokinetics after the first administration appears relevant and feasible.

Nowadays, evaluation of potential risk of metabolic drug-drug interactions (mDDIs) is of high importance within the pharmaceutical industry, in order to improve safety and reduce the attrition rate of new drugs. Accurate and early prediction of mDDIs has become essential for drug research and development, and in vitro experiments designed to evaluate potential mDDIs are systematically included in the drug development plan prior to clinical assessment. The aim of this study was to illustrate the value and limitations of the classical and new approaches available to predict risks of DDIs in the research and development processes. The interaction of cytochrome P450 (CYP) 3A4 inhibitors (ketoconazole and verapamil) with midazolam was predicted using the inhibitor concentration/inhibition constant ([I]/K(i)) approach, the static approach with added variability (Simcyp(R)), and whole-body physiologically based pharmacokinetic (WB-PBPK) modelling (acslXtreme(R)). Then an in-house reference drug was used to challenge the different approaches based on the midazolam experience. Predicted values (pharmacokinetic parameters, the area under the plasma concentration-time curve [AUC] ratio and plasma concentrations) were compared with observed values obtained after intravenous and oral administration in order to assess the accuracy of the prediction methods. With the [I]/K(i) approach, the interaction risk was always overpredicted for the midazolam substrate, regardless of its route of administration and the coadministered inhibitor. However, the predictions were always satisfactory (within 2-fold) for the reference drug. For the Simcyp(R) calculations, two of the three interaction results for midazolam were overpredicted, both when midazolam was given orally, whereas the prediction obtained when midazolam was administered intravenously was satisfactory. For the reference drug, all predictions could be considered satisfactory. For the WB-PBPK approach, all predictions were satisfactory, regardless of the substrate, route of administration, dose and coadministered inhibitor. DDI risk predictions are performed throughout the research and development processes and are now fully integrated into decision-making processes. The regulatory approach is useful to provide alerts, even at a very early stage of drug development. The 'steady state' approach in Simcyp(R) improves the prediction by using physiological knowledge and mechanistic assumptions. The DDI predictions are very useful, as they provide a range of AUC ratios that include individuals at the extremes of the population, in addition to the 'average tendency'. Finally, the WB-PBPK approach improves the predictions by simulating the concentration-time profiles and calculating the related pharmacokinetic parameters, taking into account the time of administration of each drug - but it requires a good understanding of the absorption, distribution, metabolism and excretion properties of the compound.

No abstract

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.Electronic supplementary materialThe online version of this article (10.1007/s00213-017-4792-5) contains supplementary material, which is available to authorized users.