Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy

Abstract

Genetic factors contribute to the phenotype of drug response, but the translation of pharmacogenetic outcomes into drug discovery, drug development or clinical practice has proved to be surprisingly disappointing.

Pharmacogenetics in Clinical Practice

“…(Riedlová and Richterová, 2008;Ginsburg and Willard, 2009). Table 2 contains a list of some clinically valid pharmacogenetic biomarkers and level of recommendation for related drugs in the context of FDA-approved drug labels (FDA -food and drug administration) and EMA recommendation (Gervasini et al, 2010).…”

“…A functional polymorphism was identified in the UGT1A1 gene (UGT1A1*28); this allelic variant consisted of an extra TA repeat (7 versus 6) in the promoter sequence and was associated with decreased glucuronidation rate. Carriers of the *28 are more susceptible to irinotecan-induced toxicity (Gervasini et al, 2010). Another example of pharmacogenetic testing is genotyping of gene for thiopurine S-methyltransferase (TPMT) before the treatment by thiopurines (e.g.…”

“…This is the case for cetuximab, a monoclonal antibody having activity in the therapy of advanced colorectal carcinoma and in a variety of epithelial tumor types expressing the epidermal growth factor receptor (EGFR). Also trastuzumab, a monoclonal antibody that should be used only in patients with metastatic or early breast cancer whose tumors have either HER2 over expression or HER2 gene amplification as determined by an accurate and validated assay (Gervasini et al, 2010). An extensive interindividual variability in drug response and voluntary use of opioid analgesic is well known for a long time.…”

“…With respect to pharmacokinetics, the highest level of polymorphism is found in genes involved in drug metabolism; phase I metabolism of approximately 40% of clinically used drugs occurs via polymorphic enzymes (Phillips et al, 2001). Currently, the most important polymorphic enzymes are the cytochrome P450 (such as CYP2D6, CYP2C9, CYP2C19, CYP2C8, CYP3A4, CYP3A5), thiopurine methyltransferase (TPMT), uridine diphosphate glucuronosyltransferases (especially UGT1A1, UGT1A4, UGT2B7), N-acetyltransferase 2 (NAT2), dihydropyrimidine dehydrogenase (DPD) and organic cation transporter 1 (OCT1) (IngelmanSundberg, 2004;Slanar, 2005;Gervasini et al, 2010;Becker et al, 2011;Luxembourg et al, 2011). However, genes unrelated to the pharmacokinetic properties of the drugs are nowadays also known to affect the therapeutic performance or safety of the medicines.…”

Pharmacogenetics Role in Forensic Sciences

“…In general, genetic factors are estimated to account for 15-30% of interindividual differences in drug metabolism and response, but for certain drugs this can be as high as 95% (Evans, 2004;Weinshilboum, 2003) ADRs may be reduced by means of the introduction of "personalized medicine", which anticipates the screening of patients for polymorphisms associated with a drug response, usually performed prior to the initiation of therapy. Despite significant progress in this field, only few drugs, such as cetuximab, dasatinib, maraviroc and trastuzumab, require a pharmacogenetic test before being prescribed: there are several gaps that limit the application of pharmacogenetics based upon the complex nature of the drug response itself (Gervasini, 2010). This kind of policy foresees the introduction of new sophisticated tests, especially in the field of genetics, like DNA microarrays or DNA chips.…”