Germline Pharmacogenetics - PGx

Indications for Testing

Pharmacogenetic testing can identify clinically significant variants that may guide drug and dose selection to develop personalized therapeutics. Applications include ^, :

• Preemptive screening: Testing a panel of genes before medication is needed to inform potential future drug selection and dosing
• Pretreatment testing: Testing a panel of genes after a diagnosis but before treatment initiation to inform drug selection and dosing
• Reactive testing: Testing specific gene(s) after treatment is initiated, typically in response to suboptimal drug reactions or ADRs

PGx recommendations do not exist for all medications. Clinicians should consult reliable, up-to-date resources to determine whether PGx guidelines are available for medications of interest.

Laboratory Testing

Pharmacogenetic testing is commonly performed using commercial panels with preselected single nucleotide variants (SNVs).  These variants are typically linked to drug response in PGx guidelines or drug labels. However, selected variants differ among panels; some panels may include only the variants most strongly associated with drug response, whereas others will include all variants with potential associations.

Panels are cost-effective and efficient but limited. They cannot detect rare or structural variants, and interpretation is constrained to the tested variants. A negative result indicates the absence of only the tested variants, not all clinically relevant ones. Next generation sequencing (NGS) testing is more comprehensive but is not yet integrated into routine clinical care. 

Initially, pharmacogenetic testing was used for reactive single-gene testing. Its use has since expanded to pretreatment testing. Preemptive pharmacogenetic screening can enable therapy optimization and reduce delays in treatment initiation ^,  but is not yet standard practice; however, it has been successfully implemented in some hospital-affiliated research programs. 

Limitations of Pharmacogenetic Testing

• PGx associations have varying levels of evidence regarding their clinical actionability, and pharmacogenetic testing and dosing recommendations may differ across guidelines. 
• PGx guidelines do not exist for all medications, and not all ADRs or therapeutic failures are caused by genetic variants. 
• Commercially available PGx panels differ with respect to the genes and variants they include, although the Association for Molecular Pathology is working to standardize the inclusion of critical PGx variants. 
• The detection of variants of uncertain significance (VUSs), if reported, results in ambiguity regarding clinical action. 
• Pharmacogenetic testing may have reduced clinical utility in certain populations due to underrepresentation of diverse ancestries in genetic reference databases, which limits variant detection and interpretation. 

Pharmacogenetic Testing Recommendations

The table below highlights examples of gene-drug pairs with pharmacogenetic testing recommendations from the FDA or multiple clinical practice guidelines. This list is not exhaustive. For a more comprehensive overview, ClinPGx’s Clinical Guideline Annotations,  ClinPGx’s Drug Label Annotations,  or the FDA’s Drug Label Annotations  are valuable resources for identifying medications with pharmacogenetic testing information.

Clinical Applications of Pharmacogenetics Information

Dosing Guidelines

The following table lists some known drug-gene pairs that have CPIC guidelines. 

Guiding Drug and Dose Selection

Pharmacogenetic testing can be used to predict optimal dosing for select drugs and avoid ADRs. 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 (e.g., phenytoin) are associated with both type A and type B ADRs.

Type A Adverse Drug Reactions

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, it's important to 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 (e.g., CYP2C9, DPD, 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 PGx may be altered by drug-drug interactions (e.g., a CYP2C9 normal metabolizer could become a poor metabolizer if the patient takes a medication that inhibits CYP2C9).

Type B Adverse Drug Reactions

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 ADR 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 warfarin dosing calculator is Warfarin Dosing.  Several other algorithms have also been developed for prescribing and dosing warfarin. 

Many CPIC guidelines 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 PGx findings are also available in the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling. 

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 an ADR or a failure to respond is based on clinical factors, the clinical scenario (e.g., whether a reaction is likely to be related to the drug and/or dose administered), compliance, the drug, and the drug formulation.