Objective
The importance of biotransformation in determining the intensity and duration of the effects of drugs in man has long been recognised. Individuals can vary markedly in their metabolism of drugs and by the mid-1970s it was quite clear that this was due to both genetic and environmental factors. This led to important questions as to how new drugs should be evaluated for their metabolism and kinetics in man. Should this be in a panel of individuals selected randomly from the population, as was normal practice at that time or should there be some attempt to define the metabolic characteristics of the subjects prior to entry to Phase 1 and Phase 2 studies ?
The seminal work on genetic factors affecting drug metabolism in man was performed in Europe and it was therefore entirely appropriate that a European programme be established to investigate the criteria for the choice and definition of healthy volunteers and/or patients for Phase 1 and 2 studies in drug development. Such a proposal was made to the senior officials of COST and was accepted with the result that the MoU for COST Project B1 was signed on 24 Feb 1986, by six countries. At the end of Round I, 12 countries were participating in this concerted Action.
The main emphasis during Round I was to harmonise new information on genetic differences in the cytochrome P450 system and to develop in vitro approaches to the prediction of variability in human drug metabolism. These activities culminated in the publication of a number of position papers, which have since been widely cited, and a consensus conference on pharmacogenetics in Besançon in October 1989.
The Management Committee of COST B1 was convinced of the importance of metabolic and kinetic studies in man in the drug discovery and development process. It was clear that through its actions COST B1 could rationalise much of the relevant on-going research in Europe. The Management Committee therefore proposed that the project be renewed.
This was agreed by the Committee of Senior Officials of COST so that Round II of the project, subtitled "The role of metabolic and kinetic studies in drug research and development", commenced on, 24 Feb 1991, and continued until 23 Feb 1995.
During the second round the project has focused on newer aspects of genetic factors, the influence of environmental factors on variability in drug metabolism, the continued development of in vitro approaches, and the evaluation of population approaches to kinetics, in particular the availability of suitable software. These topics have been the subject of a number of expert meetings and have stimulated the production of several critical reviews.
The Management Committee has identified for the Round III 1995/98 four related key areas that would benefit immensely from further co-operation, to aid in the development and use of more effective, safer and less expensive drugs. These are all related to the identification, quantification and management of the sources of variability in drug elimination and effect on man. The four areas are as follows :
Assessing drug metabolism in man
During Rounds I and II of COST Action B1, the Management Committee focused effort on in vitro approaches to drug metabolism and the characterisation of genetic and non-genetic sources of variability in drug metabolism. These topics have now developed considerably and there is a real need for a European consensus on the rational application of these approaches in pre-clinical drug evaluation. The utility of studies in vitro, utilising subcellular fractions, isolated cells, tissue slices and recombinant expressed enzyme systems of human origin in predicting routes and rates of drug metabolism and factors influencing these (both genetic and non-genetic, including pathophysiological factors) will be assessed. Such approaches hold enormous potential for improving current procedures for preclinical studies and could reduce animal use considerably. Methods for evaluating the activity of individual members of multi-gene families of drug metabolising enzymes in vivo, utilising selective substrates and inhibitors will be recommended. Protocols will be developed for identifying potential drug-drug interactions resulting from induction of inhibition. Work will continue on the detection of those drugs influenced by genetic factors and the consequences of this.
Integrated pharmacokinetic/pharmacodynamic approaches to drug development
At present, dose-response trials are the predominant means of establishing optimum dosing regimens. In recent years it has been recognised that it is important to incorporate measurements of the active concentration of the drug into the design as this approach allows consideration of the impact that variability due to genetic, age, disease, co-medication and environmental factors can have on outcome. In order to improve the predictive power of dose-finding studies it is essential to explore the relationship between dose, plasma concentration and drug effect, which takes into account the fact that, just as the kinetics of a drug are subject to variability, so too is the response. There is a need to promote integrated pharmacokinetic/pharmacodynamic approaches in drug development, based on the identification of appropriate end points to reflect effect followed by biomathematical modelling of the relationship between drug or metabolite concentrations and the intensity of pharmacological effect. Methods for the quantification of pharmacological response in vivo, both in pre-clinical animal models and in humans will be developed. Biomathematical models of the time course for drug action will be produced. Finally, the application of such integrated approaches will be fostered in academia and the pharmaceutical industry.
Population approaches in drug development
Inter-individual variation in drug response, due to both drug disposal and drug effect, is a major problem in drug therapy and much effort is now devoted in trying to identify the sources of such variability during drug development. Often, this involves studies in relatively small numbers of target groups, such as the elderly, those in renal failure or with hepatic disease. This approach requires prior identification of factors likely to contribute significantly to variability. Once drugs enter clinical trials, where variability will be at a maximum, the data obtained on individual patients are often sparse and hence it is not possible to characterise an individual's pharmacokinetics and pharmacodynamics. The recently developed statistical methods that permit integrated information on pharmacokinetics and pharmacodynamics to be obtained from such data, using so-called population approaches, provide considerable benefits.
These may limit the need for non-patient data, and help improve the effectiveness of the clinical evaluation programme. It may also be possible to identify sub-populations exhibiting atypical kinetics or responses. Notwithstanding the potential benefits of this approach it is still in its infancy. During Round III, a European "pool of expertise" will be created from amongst scientists in the pharmaceutical industry, academia, clinical research, software developers, and regulatory agencies. Three major areas will be addressed : software development and dissemination of information related to its application, study design appropriate for population analysis, and the fostering of research into mixed-effects modelling.
4. Post-marketing linkage of variability in pharmacokinetics with drug response and adverse reactions
When a new drug is first marketed, the full extent of its pharmacokinetic and pharmacogenetic variability, and the potential of enzyme specific drug-drug interactions have seldom been fully elucidated. Although the approaches described above would help improve this situation markedly, the possible clinical impact of such factors on drug response and more particularly on adverse reactions may still remain unresolved for several years, as is often the case at present. After a drug's release for general use, a wide spectrum of patients is exposed, including "at-risk" groups not normally studied in pre-marketing trials.
Although a proportion of adverse reactions are reported in the first few years of use, the possible importance of pharmacokinetic and genetic variability is seldom recognised. Thus, strategies need to be developed that make it possible, at an early stage, to identify aberrant drug response or adverse reactions arising as consequence of pharmacokinetic or pharmacogenetic variability. Schemes for the systematic examination and reporting of cases where such variability might be involved in therapeutic failure or drug toxicity will be devised. This will require the prospective and retrospective application of the approaches described above for characterising the activity and phenotype/genotype of the major drug metabolising enzymes in patients. The widespread availability of techniques for phenotyping or genotyping for the common polymorphisms of drug metabolism will be promoted. The value of coupling such approaches to post-marketing surveillance programmes, preferably European-wide collaborative schemes, will be investigated. Particular attention will be paid to the possible contribution of ethnic differences in pharmacokinetics or pharmacogenetics to aberrant drug response, tolerability and toxicity.
The effects of drugs vary from one subject to another. The purpose of the clinical evaluation of new drugs is to find doses which produce adequate therapeutic effects in most patients without toxic side effects. These doses are defined on the basis of studies in small numbers of health volunteers and patients during phase I and II testing new drugs.
Healthy volunteers and patients should be chosen according to biological criteria which facilitate a better understanding of interindividual variability in the effects of the drug under study. With this information, physicians can feel more confident that a drug which has been given marketing authorization can be safely administered when appropriate.
Current status
A Third and final Round of COST Action B 1 subtitled "Predicting and Managing Variability in the Kinetics and Effects of Drug during their Discovery, Development and Use " (DocCOST 314/94) was proposed to the COST Committee of Senior Officials. At their meeting on 24 Jan 1995 this Committee decided to prolong COST Action B1 for three years (1995/98) All Working groups have organised WG meetings and the progress has been reported to the meetings of the Management Committee. The Committee will present a Final Report in October : COST Action B 1 : Scientific and Political Impact : A Review of 10 Years of a Biomedical Action Within the Framework of COST
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