Gene:

VKORC1

vitamin K epoxide reductase complex, subunit 1

Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing.
Julie A. Johnson, Li Gong, Michelle Whirl-Carrillo, Brian F. Gage, Stuart A. Scott, C., Michael Stein, Jeffrey L. Anderson, Stephen E. Kimmel, Ming Ta Michael Lee, Munir Pirmohamed, Mia Wadelius, Teri E. Klein, and Russ B. Altman. Clinical Pharmacology & Therapeutics (2011) Oct;90(4):625-629.

Download: article and supplement

Pharmacogenetic algorithm-based warfarin dosing

Excerpt from the warfarin dosing guidelines:

Numerous studies have derived warfarin dosing algorithms that use both genetic and non-genetic factors to predict warfarin dose [Article:18305455, 19228618, 18574025]. Two algorithms perform well in estimating stable warfarin dose across different ethnic populations; [Article:18305455, 19228618] these were created using more than 5,000 subjects. Dosing algorithms using genetics outperform nongenetic clinical algorithms and fixed-dose approaches in dose prediction [Article:18305455, 19228618].

The best way to estimate the anticipated stable dose of warfarin is to use the algorithms available on http://www.warfarindosing.org (offering both high-performing algorithms [Article:18305455, 19228618]). The dosing algorithm published by the International Warfarin Pharmacogenetics Consortium is also online, at http://www.pharmgkb.org/do/serve?objId=PA162372936&objCls=Dataset#tabview=tab2. The two algorithms provide very similar dose recommendations.

Download: IWPC Pharmacogenetic Dosing Algorithm

Approach to pharmacogenetic-based warfarin dosing without access to dosing algorithms

Excerpt from the warfarin dosing guidelines:

In 2007, the FDA modified the warfarin label, stating that CYP2C9 and VKORC1 genotypes may be useful in determining the optimal initial dose of warfarin [Article:17906972]. The label was further updated in 2010 to include a table (Table 1) describing recommendations for initial dosing ranges for patients with different combinations of CYP2C9 and VKORC1 genotypes.

Genetics-based algorithms also better predict warfarin dose than the FDA-approved warfarin label table [Article:21272753]. Therefore, the use of pharmacogenetic algorithm-based dosing is recommended when possible, although if electronic means for such dosing are not available, the table-based dosing approaches (Table 1) are suggested. The range of doses by VKORC1 genotype and the range of dose recommendations/predictions by the FDA table and algorithm are shown in Figure 2.

Figure 2 Legend: Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics Consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1*1 for US Food and Drug Administration (FDA) table and algorithm dosing). The range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. The range of doses predicted using the IWPC dosing algorithm in these 3,616 patients is shown by the solid lines.

Figure 2 demonstrates that the range of individuals covered by the FDA table is much narrower than that of the algorithm. The article and supplement detail important variables that are not covered by the table that should also be taken into consideration.

Table 1: Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based on CYP2C9 and VKORC1 genotype using the warfarin product insert approved by the United States Food and Drug Administration:

Reproduced from updated warfarin (Coumadin®) product label.

Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for acenocoumarol based on VKORC1 genotype (PMID:21412232). They found that VKORC1 genotype contributes to dose variability. However, they make no dosing recommendations at this time "because of strict international normalized ratio monitoring by the Dutch Thrombosis Service."

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenprocoumon based on VKORC1 genotype (PMID:21412232). They found that VKORC1 genotype contributes to dose variability. However, they make no dosing recommendations at this time "because of strict international normalized ratio monitoring by the Dutch Thrombosis Service."

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The FDA recommends genetic testing prior to initiating treatment with warfarin.

Excerpt from the warfarin drug label:

The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.

The VKORC1:G-1639A polymorphism is associated with lower dose requirements for warfarin in Caucasian and Asian patients. Increased bleeding risk and lower initial warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3 alleles. Approximately 30% of the variance in warfarin dose could be attributed to genetic variation in VKORC1, and about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms. Accounting for genetic variation in both VKORC1 and CYP2C9, age, height, body weight, interacting drugs, and indication for warfarin therapy explained about 55% of the variability in warfarin dose.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the warfarin drug label. Pharmacogenomics-related dosing information is found in Table 5 on page 27.