[How to individualize drug therapy based on pharmacogenetic information? A systematic review of published guidelines]

Abstract

Background | Differences (polymorphisms) in genes encoding drug targets, drug transport proteins, or drug metabolizing enzymes may be responsible, among other factors, for the observed variation in patients' responses to medications. The field of pharmacogenetics aims to identify patients at higher genetically-determined risk of adverse effects or poor response to medication. This information would allow for modification of dosage or substitution with alternative therapy. However, there is a lack of awareness of pharmacogenetic clinical practise guidelines. Methods | A systematic literature review was conducted, using the Medline and PharmGKB databases, which focused on published guidelines for dosage modification or selection of drugs based on germline mutations in genes with pharmacokinetic or pharmacodynamic impact. Prescribing information from the European Medicines Agency, the German Federal Institute for Drugs and Medical Devices, and the US Food and Drug Administration was also screened for pharmacogenetic guidance. Results | The literature review revealed 20 guideline publications elucidating 43 drugs with recommendations for genotype-guided prescribing. Moreover, drug labels for 37 drugs also contained genotype-guided prescribing recommendations, some of which were linked to optional or obligatory pre-therapeutic pharmacogenetic testing. Conclusions | Existing guidelines for genotype-based drug prescribing are rarely derived from prospective, controlled trials; thus, their level of evidence is usually low. Even with low-quality evidence, strong recommendations can be made in favour of pharmacogenetic modification of prescription, such as for abacavir and the HLA-B genotype, if there is a large and certain difference between the benefits and harms. For other drug-gene pairs, such as vitamin K antagonists and CYP2C9/VKORC1, the net benefit from the pharmacogenetic-based dosing strategy is small and matter of debate. Because pharmacogenetics is playing a growing role in drug development and pre-prescription genotyping will become more widespread, specific pharmacogenetic guidance for treating physicians will become increasingly important.