for Physical Chemists by Physical Chemists

18.00 – 19.00

Registration, welcome drinks

19.00 - 19.45

Keynote Lecture: Oral biopharmaceutics tools for the pharmaceutical industry
Prof Clive Wilson (University of Strathclyde)

The input function between drug release and the plasma concentration-time profile has been likened to a black box: an amplifier with a non linear response and whose mechanical functions are poorly understood. At the biological level the behavior of the system is difficult to predict and so as scientists we need to generate in vitro tools that allow us to bridge the in vivo to the in vitro gap. But what does the in vivo environment look like... and how could we simulate the whole picture in silico to predict drug product performance?

To understand the absorption of drugs, we need to deconvolute dissolution of the drug product from the absorption function. The dissolution process involves metastable states, supersaturation and precipitation; the absorption state input and efflux and metabolism. Within the development of the global understanding of these processes we need new instruments to dissect the processes. Advancements will be made from new imaging technologies, a better understanding of the in vivo environment and a construct that identifies performance-critical attributes.

20.00

Symposium Dinner

9.00 – 9.20

Late Registration

9.20 – 9.30

Welcome

9.30 – 10.15

Drug-likeness is a key consideration when selecting compounds during the early stages of drug discovery. However, the use of rules to assess compound quality in absolute terms does not adequately reflect the whole spectrum of compound quality and may inadvertently foster undesirable molecular property inflation. We have developed QED (quantitative estimate of drug-likeness), an empirical measure that reflects the underlying distribution of molecular properties and may also capture the abstract notion of aesthetics in medicinal chemistry.

A second topic addresses the harnessing of medicinal chemists experience to manually apportion large numbers of compounds as acceptable or otherwise which is routinely used as part of both library design and hit triage. There is increasing evidence to suggest that such assignments can be somewhat inconsistent. To address this issue we have developed ChemSmash, an online, crowd-sourced assessment of several thousand compounds by a large cohort of experienced medicinal chemists, which uses pairwise compound assessments to rank compounds by their perceived chemical attractiveness.

10.15 – 11.00

Screening of compounds in early ADMET assays presents an interesting challenge from the CRO perspective. Most large companies have preferred parameters for screening compounds, and there is little consensus on methodology across and sometimes within organisations. The development of assays in pharmaceutical companies has been driven by disease area worked in, availability of particular technologies or personal preference. However when outsourcing, a critical consideration is to ensure consistency across in house and outsourced assays.

The flexibility to screen under client-specified conditions is key to how Cyprotex has chosen to operate, rather than attempting to dictate the assay design to the client. This presentation discusses some of the differences observed, detailing approaches taken and industry trends from a Cyprotex perspective. The second part discusses how this flexibility is technically achieved using dynamic control of robotics, analytics and automatic results generation. Finally, some new early stage screening assays are presented.

Coffee and Posters

11.30 – 12.15

Since the implementations of HT methods in the field of ADMETox in the late 90s of the last century, hundred thousands of results have been stored in databases of pharmaceutical companies. While in the beginning the focus was very much on the development and further miniaturization of individual assays, priorities changed quickly when drug discovery teams got confronted with the interpretation and decision making of the data coming from the various HT assays. Besides that, more sophisticated strategies have been worked out since it was realized that not all assays are equally important to all projects in all phases of drug discovery and development.

In the last years, pharmaceutical industry is very much forced to streamline their processes since the overall number of NMEs remains constant while at the same time, costs and the time needed to develop new drugs exponentially increases. Hence, the question arises what assays need to be maintained, which in silico tools are sufficiently good to replace in vitro assays and how we can benefit from the knowledge that has been generated over the years and finally how this influences both the development of new assays/in silico tools as well as new optimization strategies for our development projects.

In my presentation, I will show you the current status of the interplay between in silico tools and in vitro assays and how this may look like in the future based on case studies from drug discovery projects at Roche.

12.15 – 13.10

Lunch and posters

13.10 – 13.45

TIM-1 "Mechanical Man": Using the TIM-1 GI in-vitro model to understand drug absorption and its application within AstraZeneca.

13.45 – 14.20

A revised classification system for oral drugs was developed using the biopharmaceutics classification system (BCS) as a starting point. The revised system is designed to have a greater focus on drug developability. Intestinal solubility, the compensatory nature of solubility and permeability in the small intestine and an estimate of the particle size needed to overcome dissolution rate limited absorption were all considered in the revised system. The system was then validated by comparison with literature on the in vivo performance of a number of test compounds. Observations on the test compounds were consistent with the revised classification, termed the developability classification system (DCS), showing it to be of greater value in predicting what factors are critical to in vivo performance than the widely used BCS.

Tea and Posters

15.00 – 15.35

According to recent estimations, up to 90% of the new small molecular entities being developed in drug discovery suffer from low aqueous solubility according to the criteria of the biopharmaceutics classification system. Poor dissolution and/or limited intraluminal concentrations in the gastrointestinal tract can be expected to hinder the development of these compounds into drugs suited for oral administration. As a result, biorelevant estimations of gastrointestinal solubility are critical to make informed decisions concerning candidate selection and formulation development. Based on recent research at Drug Delivery and Disposition (KU Leuven), the presentation will focus on various issues related to the biorelevant profiling of drug solubility for prediction of intraluminal drug concentrations and subsequent absorption, including:

• solubility measurements in human gastric and intestinal fluids
• the use of human solubility data as reference for the optimization of simulation fluids
• beyond solubility: supersaturation and precipitation assessment in human fluids
• assessment of intraluminal drug concentrations in humans

15.35 – 16.10

The desire for in vitro tools to predict the fate of orally dosed drugs continues to grow. With this in mind, the Sirius inForm is a new platform, developed to meet these needs. By enabling the study of multiple dosage forms and sample types in innovative, biorelevant assays, the Sirius inForm aims to provide useful information about drug behaviour in the GI tract. The work presented here covers some of the data collected as part of the development process and discusses the scientific topics where we intend to contribute. Namely, the digestion of lipid based formulations, methods for measuring supersaturation and simulating the intestinal passive absorption process.

16.10 – 16.15