Advancing nonclinical innovation and safety in pharmaceutical testing.

Nonclinical tests are considered crucial for understanding the safety of investigational medicines. However, the effective translation from nonclinical to human application is limited and must be improved. Drug development stakeholders are working to advance human-based in vitro and in silico methods that may be more predictive of human efficacy and safety in vivo because they enable scientists to model the direct interaction of drugs with human cells, tissues, and biological processes. Here, we recommend test-neutral regulations; increased funding for development and integration of human-based approaches; support for existing initiatives that advance human-based approaches; evaluation of new approaches using human data; establishment of guidelines for procuring human cells and tissues for research; and additional training and educational opportunities in human-based approaches.

Optimizing drug discovery by Investigative Toxicology: Current and future trends.

Investigative Toxicology describes the de-risking and mechanistic elucidation of toxicities, supporting early safety decisions in the pharmaceutical industry. Recently, Investigative Toxicology has contributed to a shift in pharmaceutical toxicology, from a descriptive to an evidence-based, mechanistic discipline. This was triggered by high costs and low throughput of Good Laboratory Practice in vivo studies, and increasing demands for adhering to the 3R (Replacement, Reduction and Refinement) principles of animal welfare. Outside the boundaries of regulatory toxicology, Investigative Toxicology has the flexibility to embrace new technologies, enhancing translational steps from in silico, in vitro to in vivo mechanistic understanding to eventually predict human response. One major goal of Investigative Toxicology is improving preclinical decisions, which coincides with the concept of animal-free safety testing. Currently, compounds under preclinical development are being discarded due to the use of inappropriate animal models. Progress in Investigative Toxicology could lead to humanized in vitro test systems and the development of medicines less reliant on animal tests. To advance this field a group of 14 European-based leaders from the pharmaceutical industry founded the Investigative Toxicology Leaders Forum (ITLF), an open, non-exclusive and pre-competitive group that shares knowledge and experience. The ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank", which aimed to enhance the interaction with experts from academia and regulatory bodies in the field. Summarizing the topics and discussion of the workshop, this article highlights Investigative Toxicology's position by identifying key challenges and perspectives.

Pharmacological validation of a telemetric model for the measurement of bronchoconstriction in conscious rats.

INTRODUCTION: Telemetric measurement of intra-pleural pressure in conscious animals that are restrained in head-out plethysmography chambers enables determination of airway resistance. Originally proposed over 10 years ago, pharmacological validation of this technique is limited. Here airway resistance in conscious, instrumented rats was compared to measurement in anaesthetised rats via a fluid filled oesophageal catheter following administration of two different pharmacological agents. METHODS: Male rats were implanted with telemetry devices and were trained to accept the restraint of head-out plethysmography chambers. A separate group of male rats were anaesthetised, placed in a body-enclosed plethysmography chamber and were prepared with a tracheal, oesphageal and jugular vein cannulae. Methacholine or NECA were given intravenously and changes in ventilation and airway resistance were measured. RESULTS: The pressure signal obtained in the telemetered rats was found to be extremely variable. Variability was confounded by excessive struggling, particularly during the infusion periods. Misplacement of the pressure sensitive catheter tip and prior habituation to the chamber were not factors in signal variability. Consequently, no dose-response relationship to either pharmacological agent was established in this model. Dose-dependent increases in resistance to both methacholine and NECA were measured in anaesthetised rats using body-enclosed plethysmography. DISCUSSION: Given the variability of the pressure signal within and between rats, the feasibility of a model in conscious rats for the measurement of airway resistance is questioned. Improved restraint methods or alternative models in conscious animals should therefore be explored. In the meantime, assessment of airway resistance is best confined to the anaesthetised rat.