A selection of articles from European Pharmaceutical Review covering Toxicology, ADME and DMPK:


Figure 1: Schematic representation of body compartments in physiologically based pharmacokinetic modelling. Abbreviations: Qorgan: Blood flow to organ

Physiologicaly based pharmacokinetic modelling of transporters in drug discovery and development

3 September 2012  •  Pradeep Sharma and Katherine Fenner, Global DMPK, AstraZeneca R&D

Physiologically based pharmacokinetic (PBPK) models describe the different compartments (tissues) in the body linked via arterial and venous blood flow (Figure 1). The volume of each tissue and blood flows are available from literature data1-5 and PBPK models have been developed for many species including rat, mouse, dog, pig and human2,6,7. PBPK models can be applied to many aspects of the drug develop ment continuum, from drug discovery8 and into development including use in regulatory responses9. PBPK modelling is becoming a tool of choice in the pharmaceutical industry for the prediction of pharmacokinetic parameters, drugdrug interactions (DDI) and tissue distribution from in vitro data. PBPK modelling was able to become a mainstream tool in the pharma - ceutical industry with advances in in vitro metabolism techniques along with the ability to predict tissue distribution parameters or Kp values for a number of classes of compounds10-13. These models usually assume that the liver and kidney are the only organs where elimination occurs and that blood flow to these organs limits the excretion rate. Recently, with advances in in vitro techniques to study transporter proteins, the input of these data in PBPK models is becoming more commonplace.

The increasing role of toxicology in early decision making processes

The increasing role of toxicology in early decision making processes

19 April 2011  •  Eckhard von Keutz, Senior Vice President, Head Global Early Development, Bayer HealthCare

Clinical development costs are rising at an alarming rate. There is a decreasing success rate for new drug candidate approval and the duration of development is increasing. In other words, industry is spending more and getting less from current drug development efforts. In 2010, 21 new drugs were approved in the U.S., the fewest since 2007, as the Food and Drug Administration showed more willingness to delay or reject medicines with potential safety risks1. Along these lines and according to a study conducted by the Biotechnology Industry Organisation and BioMedTracker, the success rate in bringing new drugs to market has fallen. The study looked at drugs moving from early stage Phase I clinical trials to Food and Drug Administration approval between 2004 and 2010. The researchers found that the overall success rate is about one in 10, down from one in five to one in six, seen in reports involving earlier years2.

Toxicology and Pharmaceutical Industry Advanced Training (PIAT)

Toxicology and Pharmaceutical Industry Advanced Training (PIAT)

19 August 2010  •  Brian Lockwood, Director of PIAT, School of Pharmacy & Pharmaceutical Sciences, University of Manchester

Toxicology is the study of the harmful interactions between chemicals and biological systems. Man, as well as other animals and plants, is increasingly exposed to a huge variety of chemicals. These range from metals to large complex organic molecules, all of which are potentially toxic. A toxicologist must understand pathology, biochemistry, chemistry and physiology as these disciplines all contribute to the impact of a given chemical’s toxicity. Indeed the multidisciplinary nature of toxicology makes the area of toxicology a challenging yet rewarding area for research and learning. To gain a true understanding of how a chemical can disrupt a biological system and cause toxic consequences is no easy matter.

Figure 1 Overview of DILI-sim A. Schematic overview of the key biological processes represented in DILI-sim B. Overview of different modules within DILI-sim. Each module is itself a model that captures a specific area of relevant biology, pharmacology and metabolism. This modular approach to DILI-sim allows the overall model to be built in manageable, testable pieces C. Knowledge management aspects of DILI-sim. Under each of the models, the supporting evidence is explicitly captured and hence the model acts as a highly structured knowledge repository

Applying systems biology and computer simulations to predicting idiosyncratic DILI

19 August 2010  •  David Cook, Associate Director, Global Safety Assessment, AstraZeneca

Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction which accounts for a significant amount of patient suffering, including death. Currently, idiosyncratic DILI is unpredictable and as a result arises late in the drug development process or even post-marketing. The prediction of idiosyncratic DILI based on preclinical or early clinical data is a formidable challenge and this short review will discuss why and how new initiatives in systems biology and dynamic computational simulations can meet this challenge and predict the ‘unpredictable’.


Segregation of molecular mechanisms of genotoxicity and carcinogenicity across human, yeast and Salmonella species

22 February 2010  •  

Screening assays for in vitro toxicity are the way to reduce the attrition rates in the preclinical development of new drugs. Here a test battery is presented for screening of genotoxic and carcinogenic compounds by means of VitotoxTM, RadarScreen, and four human liver HepG2 cell lines with two different promoters as well as responsive element (RE) settings in combination with a luminescent read-out. The VitotoxTM assay in Salmonella is a substitute for the Ames test and the RadarScreen assay for in vitro clastogenicity. Moreover, HepG2 assays with RAD51C and Cystatin A promoters, and p53-RE are more predictive for in vivo clastogenicity. The Nrf2-RE can be used for analysis of reactive oxygen species production. The validity of this battery is checked for 62 compounds of an ECVAM list for genotoxicity and for 190 other references or in house drugs.


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