Metabolic phenotype prediction from genotyping data: a bottleneck for the implementation of pharmacogenetics in drug development and clinical practice.

Abstract

Besides several adverse drug reactions and tissue-tumor markers, variability in drug metabolism is so far the cornerstone in interindividual variability in drug response and pharmacogenetics. Metabolizing enzymes account for 80% of the genes/enzymes that are mentioned for pharmacogenetic purpose on current drug labels [1]; 32% of European Medicines Agency (EMA)-authorized drugs contain pharma cogenetic information on the drug label [2]. According to drug regulatory recommendations [1], metabolic phenotyping is a crucial step for both phases of drug development: preclinical and clinical. In addition, the metabolic phenotype plays an important role for clinical implementation and pharmacovigilance throughout the study of pharmacokinetic drug-drug interactions and individualization of drug dosages. In conclusion, metabolic phenotyping is imperative for drug development: drug metabolism and pharmacogenetics are the main constituents of both the preclinical and clinical phases of drug development. Moreover, it is the key aspect for the use of pharmacogenetics in most pharmacovigilance or clinical implementation programs. For example, EMA has recently published an extensive Guideline of Pharmacogenetics and Pharmacokinetics for drug development and another one for pharmacogenetics and pharmacovigilance [1]. Lack of correlation between phenoand genotypes (“measured” and “predicted” phenotypes)