Safety Pharmacology Society: 7th Annual Meeting

Abstract

Sir James Black, the 1988 recipient of the Nobel Prize for the invention of propranolol and cimetidine, opened the 2007 Safety Pharmacology (SP) Society annual meeting with a lecture on his half-century of professional life entirely dedicated to a quest for novel drugs. The translational power of SP experimental results to humans and emerging SP trends then became the leitmotifs of the meeting. Hence, expertly generated in vitro and in vivo non-clinical data were shown to satisfactorily predict the outcome of thorough QTc interval studies in volunteers. In keeping with this theme, torcetrapib, a cholesterol esterase transfer protein inhibitor aimed at treating atherosclerosis in a novel way (raising high-density lipoprotein-cholesterol and lowering low-density lipoprotein-cholesterol levels), was shown to produce blood pressure and aldosterone increases in laboratory animals. These off-target effects, occurring also in patients, are probably one of the several mechanisms responsible for the ∼ 37% higher, treatment-related, mortality in the very large ILLUMINATE Phase III trial. This disastrous outcome forced the sponsor to suspend the clinical development of this drug, which clearly exerted the desired pharmacological activity in atherosclerotic patients. The translational potential of the core battery strategy recommended by the S7A guideline for determining respiratory liability was shown to be unsatisfactory since it does not consistently capture the airway obstructive activity of clinical candidates. However, this drug's hazardous off-target property is easily captured by performing a pulmonary respiratory resistance assay. Drug-induced QT interval shortening was presented as an emerging cardiovascular safety issue meriting SP scrutiny, as individuals harbouring inherited short QT syndromes can experience syncope and lethal ventricular fibrillation. However, any regulatory intervention on this issue would appear to be untimely, as robust human electrocardiogram data on such drug classes are still lacking. Nevertheless, the pharmaceutical industry cannot presently evade the ethical and regulatory obligations to conscientiously identify and characterise prospective drug-related risks in the framework of benefit, management and minimisation. Future challenges for SP concern the development of unambiguous assays for assessing risks intrinsic to novel therapeutic classes, formulated drug combinations and the use of medicines for specific pathological conditions. In addition, SP should actively and skilfully integrate new promising technologies, such as physiological pharmacokinetic/pharmacodynamic analysis, that can improve the translational power of non-clinical assays, as this will strengthen the prognostic value of SP as discipline striving to ensure the human safety of medicines.

Keywords::

• drug discovery
• ethical obligations
• non-clinical data
• pharmaceutical industry
• respiratory system safety
• risk management
• safety pharmacology
• torcetrapib safety issues
• translation

Acknowledgements

The author thanks H Holzgrefe for thoroughly and patient reviewing and improving this text. Thanks are extended to M Walker for helping in preparing the section on Sir James Black, and to K Bruse, D Fitzegerald, A Fossa, D Murphy, PKS Siegl and WS Redfern for critically reading certain sections of the manuscript and to TG Hammond, M Malik, D Murphy, PKS Siegl, WS Redfern and R Wallis for generously providing their presentations, indispensable in the preparation of this report. The Author assumes responsibility for full content of this report, particularly for any portion that may not accurately reflect the presentation.