Germline Pharmacogenetics - PGx

Indications for Testing

Pharmacogenetic testing may be indicated to:

• Identify clinically significant variants that may guide drug and dose selection to develop personalized therapeutics
• Predict or explain variant pharmacokinetics and/or pharmacodynamics of specific drugs as evidenced by repeated ADRs, such as treatment failures or drug-related toxicities

Guiding Drug and Dose Selection

Pharmacogenetics can be used to predict optimal dosing for select drugs and to avoid ADRs in patients. ADRs include both therapeutic failure and potentially life-threatening toxicities. ADRs are classified as type A (dose dependent) and type B (not dose dependent). Some drugs (eg, phenytoin) are associated with both type A and type B ADRs.

Type A ADRs

Drugs are administered in either active or inactive forms. Type A ADRs occur in response to the dose of a drug, and when the active drug accumulates instead of being eliminated as expected. The target dose of a drug can be adjusted to compensate for differences in active drug accumulation and elimination, thereby minimizing or preventing type A ADRs.

​For appropriate dose adjustments, first determine whether the risk of an ADR is due to the patient receiving too much of an active drug (toxicity) or not enough of an active drug (therapeutic failure).

Two mechanisms can reduce the amount of an available active drug: (1) transport of a drug away from the site of action, or (2) metabolism. Drug metabolism is frequently accomplished through drug-metabolizing enzymes (eg, CYP2C9, DPYD, TPMT, and UGT1A1). The reactions mediated by the drug-metabolizing enzymes can convert an active drug into an inactive form. Metabolic reactions can also transform an inactive drug into an active drug or can change an active drug into another active drug.

The associations between the effect of a gene variant on the activity of a specific drug, the target therapeutic dose of that drug, and the likelihood of an ADR are applied in pharmacogenetic testing to personalize drug therapy.

Note: The metabolic phenotype predicted by pharmacogenetics may be altered by drug-drug interactions (eg, a CYP2C9 normal metabolizer could become a poor metabolizer if the patient takes a medication that inhibits CYP2C9).

Type B ADRs

Type B ADRs occur when a person who has inherited a specific gene variant is administered a trigger drug. These reactions can occur regardless of dose; therefore, patients at risk for a type B reaction are advised to avoid drugs that could trigger the reaction. Examples include abacavir in patients with the HLA-B*5701 allele, as well as carbamazepine or phenytoin in patients with the HLA-B*1502 allele. In both of these examples, patients who carry at least one affected HLA-B allele are at risk for the associated ADR and should avoid these drugs.

Dose Optimization

Therapeutic or loading doses can be calculated for some drugs based on a combination of well-studied pharmacogenetic, demographic, and clinical factors, as well as common drug-drug interactions. The goal of dose calculators and algorithms is to prevent type A ADRs. For example, dose calculators can assist in both reducing the time required to achieve a therapeutic response to the anticoagulant drug, warfarin, and lowering the risk of life-threatening bleeding or thrombosis.

An example of a well-respected dose calculator is found at www.WarfarinDosing.org,  a free website that estimates dosing for warfarin. Several other algorithms  have also been developed for prescribing and dosing warfarin.

Many of the gene-based dosing guidelines  developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) provide recommended adjustments to standard dosing based on the predicted metabolic phenotype. For example, it is recommended that a 25% reduction in the standard dosing of phenytoin  be considered for a CYP2C9 intermediate metabolizer, and that a 50% reduction in the standard dosing of phenytoin be considered for a CYP2C9 poor metabolizer. Similar recommendations for dose adjustments based on pharmacogenetic findings are also available in the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling. 

Resources for Dosing Guidelines

Dosing guidelines for certain drugs are available from the CPIC  and the Pharmacogenomics Knowledgebase (PharmGKB). 

Monitoring for Therapeutic Failure

Drug therapy and dosing should be monitored by clinical exams, biomarker testing, and/or by determining concentrations of drugs and drug metabolites in biological specimens. Monitoring tools are drug and patient specific.

Posttherapeutic evaluation of ADRs or failure to respond is based on clinical factors, the clinical scenario (eg, whether a reaction is likely to be related to the drug and/or dose administered), compliance, the drug, and the drug formulation.

Pharmacogenetics Term Definitions

Drug-Gene Pair Examples

Pharmacogenetic testing can be performed by interrogating targeted genetic variants or by phenotype testing (eg, to evaluate enzyme function, protein expression, or concentrations of drugs and drug metabolites in biological specimens). The following table includes a list of some known drug-gene pairs. The FDA provides additional examples and information in its Table of Pharmacogenetic Associations.