Clinical Applications

In the recently published book (6), the clinical applications of pharmacogenomics are classified according drug group, specialties, and diseases including opioids, pain management, nicotine addiction, HIV treatment, immunosuppressants, psychiatry, and clinical and forensic toxicology. Another previous publication by Jicinio and Wong (4) offered extensive basic and clinical information for pharmacogenomics. Readers are directed to these references for detail. Other important and emerging areas include cancer, cardiovascular disorders, and hematology. It would be important to recognize the role of therapeutic drug monitoring (TDM) as a global phenotypic index including contributing pharmacokinetic, pharmacodynamic, drug-drug interaction, and other environmental factors. Thus, pharmacogenomic biomarkers might be readily characterized as an adjunct to enable the practice of personalized medicine. In order to update on these applications, a summary of recent examples would include pharmacogenomics for warfarin therapy and the treatment of colorectal cancer by irinotecan.

Warfarin, an antithrombotic agent, has narrow index and large inter-individual variation. Recent publications proposed a new dosing regimen based on pharmacogenetics of genes of CYP 2C9 and vitamin K epoxide reductase complex protein 1 (VKORC1) (35,41,42). Warfarin is racemic, with the active enantiomer, S-warfarin metabolized by CYP 2C9. Variant CYP 2C9*2 and CYP 2C9*3 correspond to decreased enzyme activities. For Caucasians, the prevalence of extensive, intermediate, poor, and ultra-rapid metabolizers are 58, 38, 4, and 4-18%, respectively. CYP 2C9 genotype accounts for 6-10% of warfarin dosing variability (40,41). VKORC1 mediates the reduction of vitamin K, and its genetic variations account for 25% of warfarin dose variability. Mean dose for VKCORC1 A/A, A/B, and B/B genotypes are 2.7, 4.8, and 6.1 mg/day (35). The additional contribution from CYP 2C9 and non-genetic factor account for up to 60% of warfarin variability (42). A dosage adjustment model is proposed along with International normalized ratio (INR) measurement with dosage reduction to 33% for CYP 2C9 *3/*3 genotype.

In using pharmacogenomics for cancer, the latest example is the FDA-approved test for uridine diphosphate-glucuronosyltransferase 1A1 (Third Wave Technologies, Madison, WI) for stratifying patients undergoing colorectal cancer treatment with irinotecan. UGT1A1 medicates the conjugation of irinotecan active metabolite, SN-38 to a glucuronide metabolite (43-46). Individual homozygous for UGT1A1*28 allele would have reduced enzyme activity, therefore requiring lower dose.

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