Relevance of pheno- and genotyping in clinical drug development.
Individual variability in the plasma concentration of a xenobiotic is a considerable problem in the clinical use as well as in the clinical development of a new drug. In clinics altered drug response and drug toxicity are predominant findings. In clinical development (especially in the early phases) problems with the interpretation of individual pharmacokinetics and appearance of unexpected drug reactions may occur. One major reason for the inter-and intraindividual variability is based on variations in the metabolism of the drug that are dependent on the genetic variations of the metabolising enzymes. However, while the first of these so-called polymorphisms has already been described in 1979 (for a review see [Daly 1995]) and knowledge of these polymorphisms are still growing, the impact on clinical practice as well on the selection and development of drug candidates in the pharmaceutical industry at present is still limited. This may change in the near future as recent advances in molecular biology and especially in the diagnosis of individual genomic characteristics will result in a better understanding of the basic principles of the polymorphisms. High throughput screening methods will reveal information on the distribution of these polymorphic alleles in the target population and enable the broad characterization of the drug candidate in in vitro systems. The early knowledge as to whether a polymorphic pathway is involved in drug metabolism/action and of its clinical relevance will lead to a reduction of time and costs in the development of a new drug.
Zühlsdorf
M T
MT
Department of Pharmacodynamics 1, Institute of Clinical Pharmacology, Pharma Research Centre, Bayer AG, Wuppertal, Germany.
D003663:Decision Trees; D015195:Drug Design; D004341:Drug Evaluation; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D010599:Pharmacokinetics; D010600:Pharmacology; D010641:Phenotype; D011110:Polymorphism, Genetic; D015262:Xenobiotics / Q000378:metabolism
D015262:Xenobiotics