The Role of Pharmacogenetics in Antithrombotic Therapy Management: New Achievements and Barriers Yet to Overcome.

BACKGROUND: Pharmacogenetics investigates the response to pharmacological treatments based on individual genetic background. Actually, numerous pharmacogenetic tests help to predict the response to drugs used in different medical areas, contributing to the so-called personalized medicine. OBJECTIVE: This review aims to update the available data on the genotype-guided treatment with both the anticoagulant and antiplatelet agents. Moreover, it sheds light on the pitfalls in the implementation of cardiovascular pharmacogenetics. METHODS: A review of the literature on the studies investigating the effects of the genotype- guided anticoagulant and antiplatelet treatment was performed. RESULTS: Considering the extensive use of antithrombotic drugs, pharmacogenetics has particular importance in this field. Several polymorphisms influence the response to both anticoagulant and antiplatelet agents, and tests, based on their identification, are now available. CONCLUSION: Recent randomized clinical trials demonstrated that pharmacogenetics might successfully contribute to optimizing the antiplatelet therapy also in patients particularly complicated to treat. However, despite accumulating evidence on the utility and feasibility of some pharmacogenetics tests, several barriers still exist in their implementation in clinical practice.

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.