Example: Warfarin, a vitamin K antagonist, is the oldest and most widely prescribed oral anticoagulant worldwide. Within a narrow therapeutic range, warfarin is highly effective for the prevention and treatment of thromboembolic disorders (Chapter 34). Nevertheless, interpatient differences in dosing requirements (up to 20-fold) often lead to complications from subtherapeutic anticoagulation and clotting or supratherapeutic anticoagulation and bleeding, which are among the most common causes for emergency room visits in the United States. Understanding the factors that contribute to variability in individual warfarin maintenance doses may improve therapeutic outcomes.
Warfarin dosing algorithms that include clinical and known genetic influences on warfarin dose, ie, polymorphisms in CYP2C9 and VKORC1, clearly outperform empiric-dosing approaches based on population averages, as well as dosing based on clinical factors alone (Table 5–2). The pharmacologic action of warfarin is mediated through inactivation of VKORC1, and since the discovery of the VKORC1 gene in 2004, numerous studies have indicated that individuals with decreased VKORC1 expression, eg, carriers of the -1639G>A polymorphism, are at increased risk for excessive anticoagulation following standard warfarin dosages. Furthermore, warfarin is administered as a racemic mixture of Rand S-warfarin, and patients with reduced-function CYP2C9 genotypes are at increased risk for bleeding due to decreased metabolic clearance of the more potent S-warfarin enantiomer. It is predicted that gene-based dosing may help optimize warfarin therapy management and minimize risks for adverse drug reactions.
Recently, epigenomics, which is the heritable patterns of gene expression not attributable to changes in the primary DNA sequence, has become an active area of research that may provide additional insights into the causes of variability in drug response. Epigenomic mechanisms that can regulate genes involved in pharmacokinetics or drug targets include DNA methylation and his-tone modifications. Although there is still much to be understood, epigenomics may contribute to our knowledge of diseases as well as our understanding of individual phenotypes such as acquired drug resistance.
Discoveries in pharmacogenomics are increasing as new technologies for genotyping are being developed and as access to patient DNA samples along with drug response information has accelerated. Increasingly, pharmacogenomics discoveries will move beyond single SNPs to multiple SNPs that inform both adverse and therapeutic responses. It is hoped that prescriber-friendly predictive models incorporating SNPs and other biomarkers as well as information on demographics, comorbidities, epigenetic signatures, and concomitant medications will be developed to aid in drug and dose selection. CPIC guidelines and Food and Drug Administration-stimulated product label changes will contribute to the accelerated translation of discoveries to clinical practice.
Altman RB, Whirl-Carrillo M, Klein TE: Challenges in the pharmacogenomic annotation of whole genomes. Clin Pharmacol Ther 2013;94:211. Bertilsson DL: Geographical/interracial differences in polymorphic drug oxidation.
Clin Pharmacokinet 1995;29:192. Browning LA, Kruse JA: Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother 2005;39:1932. Camptosar [irinotecan product label]. New York, NY: Pfizer Inc.; 2012. Cappellini MD, Fiorelli G: Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64.