Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Safety Pharmacology, Pharmacokinetics and Toxicology.
An Obstacle Race in the Development of a Pharmaceutical Compound

A. Guzmán

Toxicology Department, Esteve

Due to their relevance for human safety, the conduct of preclinical safety and pharmacokinetic studies before the start of clinical studies and granting of marketing authorization, has become a critical, mandatory and fairly standardized field firmly regulated by national and international health authorities. As a compound progresses through the preclinical developmental program, the number, complexity and cost of the requested studies increase. Toxicologists in the pharmaceutical industry are mainly involved in the preclinical safety assessment of candidate compounds, this being a continuous process that takes place both before the start of and on course with clinical studies. The main objectives of preclinical safety/toxicity studies are to identify the toxicological potential of a compound (i.e., hazard identification), to establish a dose-effect relationship, and finally, and most importantly, to evaluate the relevance of the observed findings for the exposure of humans (i.e., risk assessment).

The objective of hazard identification is basically accomplished by the use of in vitro and in vivo experimental systems. In these studies, use is made of high doses and extended treatment periods, as compared to clinical use, in order to increase the capability of these experimental systems for detecting adverse effects. For some effects observed in preclinical studies further information can be obtained during the course of clinical studies (e.g., potential for hepatotoxicity). For some other endpoints, however, these preclinical studies will constitute the only source of information before marked authorization (e.g., developmental toxicity). Toxic effects can potentially be caused both by parent compounds and/or any generated metabolite(s). Thus, whenever possible, safety studies should be conducted in those laboratory animal species showing a metabolic profile closest to man. Pharmacokinetic characterization of the substance responsible for the toxic effect (either parent compound and/or metabolite(s)) will allow for a proper extrapolation from animal findings to human situations. For toxicologists it will be of most importance to identify unacceptable hazards as early as possible in the developmental process in order to avoid wasting time and resources. However, the results of any toxicity study must not be taken on its own but should be considered within the context of the experimental system used, the nature of the observed effects and in light of available scientific knowledge. Several examples of findings not considered of relevance for human risk assessment are available in the scientific literature.

The risk assessment process will have to take into consideration the nature of the adverse effects observed in preclinical studies, the probability that this adverse effect might occur in humans taking the drug and the severity of the disease being treated. Approval of a new compound will only be granted when the benefits outweigh the foreseeable risks for a particular indication or population. When this is the case, a statement of "safe drug" is given and passed on to the general public. However, pharmaceutical compounds are specifically designed to cause a biological effect, and thus should not be viewed as "innocuous substances". The scientific community should do its best to make the society aware of a concept that was established in the 16th century by Paracelsus, namely that there is no "safe drugs", but rather "safe use of drugs".

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com