Impact of pharmacogenetics on therapeutic drug monitoring

Abstract

Pharmacogenetics and its application to TDM is an emerging field. Valid pharmacogenomic biomarkers listed by the FDA include the drug metabolising enzymes CYP2C9 + , CYP2C19, CYP2D6, DPD, NAT, TPMT + , UGT1A1 + as well as HLA-B * 5701 + and VKORC1 + . Genomic biomarkers for which testing is recommended are marked (+). There is a lack of evidence supporting a clear association between ABCB1 (MDR1) genotype and clinical drug response or toxicity. The CYP2D6 polymorphism plays an important role for the metabolism of antipsychotic as well as antidepressant drugs and tamoxifen. Thiopurine-S-methyltransferase (TPMT) deficiency causes thiopurine intolerance accompanied with severe myelosuppression. Testing for TPMT phenotype/genotype is now a useful practice. An inosine triphosphatase mutation ( ITPA 94C>A) appears to be a further promising marker for thiopurine interolerance. A significant difference in dose-adjusted tacrolimus blood levels has been demonstrated between CYP3A5 expressors compared to non-expressors. HLA-B*5701 genotyping is useful to identify patients at greatest risk for a hypersensitivity reaction to abacavir. Genome-wide association studies are increasingly being used and, e.g., have identified SLCO1B1 variants that are strongly associated with statin-induced myopathy. Expression profiling has the potential to identify gene-expression patterns related to drug response. Both approaches may be complementary and take into account that response to most drugs is influenced by multiple genes. In addition to TDM, drug disposition marker genotyping is a promising tool for individualisation of drug dosing.