A drug has to be demonstrated to be reasonably safe and effective before it can enter the clinic (see Chapter 10 ). An integrated risk assessment will be made on the efficacy and safety of the medicine to provide a risk-benefit analysis as an interpretation of the therapeutic index (see Chapter 6 ). To ensure medicinal products around the globe have been tested to the same degree of stringency, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the governmental regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration, including guidelines to assess safety and toxicity issues. Below is a summary of the recommendations taken from the ICH guidelines ( www.ICH.org ). The scale and timing of these safety tests occur during various stages of the lifespan of the development of a drug ( Fig. 9.1 ).
The purpose of safety pharmacology during preclinical drug development is to assess the potential undesirable effects of a medicinal product on essential physiological systems (cardiovascular, respiratory and central nervous system (CNS), known as the core battery). A selection of in vitro and in vivo tests are used ( Table 9.1 ) with the following considerations:
Time course and resolution, usually from a single dose.
Evaluation of a wide range of doses to cover the anticipated therapeutic range and higher to determine at what doses adverse effects appear.
Doses that might cause toxicity are not used, since these may hide an effect on the physiological system being investigated.
Evaluation of safety is usually assessed using the proposed clinical route of administration, but other routes of administration (e.g. systemic) are sometimes also evaluated if warranted.
Appropriate negative and positive control groups used.
|Central Nervous System: Motor activity, behavioural changes, coordination, sensory/motor reflex responses and body temperature. |
Cardiovascular System: Blood pressure, heart rate and the electrocardiogram. In vivo, in vitro and/or ex vivo evaluations, including methods (e.g. use of human ether-a-go-go-related gene (hERG) that codes for the Kv11.1 alpha subunit of a cardiac potassium channel) for repolarization and conductance abnormalities.
Respiratory System: Respiratory rate and other measures of respiratory function (e.g. tidal volume or hemoglobin oxygen saturation).
Depending on the outcome of the initial core battery tests, it may be necessary to conduct further investigations to gain a meaningful understanding of a medicinal product’s effects on a particular physiological system ( Table 9.2 ).