10/7 PG of Drug Targets

Define drug target and identify common types of drug targets

Drug target: any protein involved in the pharmacological action of the drug; not just the protein to which the drug directly binds to.

Common types of drug targets include receptors, enzymes, ion channels, transporters, and immune or signaling proteins.

E.g., VKORC1 enzyme is the drug target of warfarin.

Explain how genetic variation can alter a drug target, including its expression, structure, or function.

1. Change the amount of target

   • DNA variant → altered gene expression → more or less target protein

2. Change the structure of the target

   • DNA variant → altered AA sequence → altered drug binding

3. Change target function/signaling

   • DNA variant → altered receptor/channel/enzyme function → altered response to the same drug concentration

Explain how genetic variation in a drug target can alter pharmacodynamics (PD) and individual responses to a drug or ligand.

PD = what the drug does to the body

Genetic variation in a drug target directly modifies the body's sensitivity and cellular response to a given drug concentration.

Same drug + modified target = potentially different drug response

Use the PTC taste receptor as an example of how genetic variation in a receptor produces different phenotypes.

The PTC taste receptor is expressed on taste receptor cells on tongue taste buds.

• We each have 2 copies of the PTC receptor gene - 1 from each parent.

The gene for tasting PTC is dominant (T) over the inability to taste PTC, which is recessive (t).

• TT or Tt will express the binding PTC-receptor on their taste cells → PTC can bind to receptors → can taste PTC

  • TT will taste PTC very strongly as soon as it touches tongue, while Tt will take more time.

  • Tt has 1 tasting gene and 1 non-tasting gene, so some receptors can bind PTC while others cannot.

• tt will express non-binding PTC-receptors on taste cells → PTC cannot bind to receptors → cannot taste PTC

Summary: ability to taste PTC has a very strong genetic component (SNPs)

• Shows how genotype can affect PD

• Individual differences in ability to taste PTC is similar to differences in reactions to drugs

Describe HER2 as an example of how genetic alterations in a drug target can influence response to targeted cancer therapy.

HER2: a protein expressed by certain breast cancer tumors. Her2 is encoded by the gene ERBB2.

Breast tumors are either Her2+ or Her2-

• Her2+ tumor: tumoricide (trastuzumab/Herceptin) can have a target to cause an effect.

• Her2- tumor: little to no Her2 overexpression; trastuzumab will not have a good target.

Clinical implication: genetic testing is required before using trastuzumab.

• Patient needs to test positive for Her2+ tumors

Her2 status is commonly determined from the tumor, using methods such as IHC or FISH. The clinically relevant alteration is often tumor-specific.

Distinguish pharmacogenomics of drug targets from pharmacogenomics of drug-metabolizing enzymes and transporters.

PG of drug-metabolizing enzymes and transporters mainly affect how much drug is present or where it moves (PK)

• E.g., CYP2C9 variants alter S-warfarin clearance and plasma concentration

On the other hand, PG of drug targets mainly affects how strongly the body responds to the drug (PD)

• E.g., Her2 + or - affects the tumor’s response to trastuzumab

Describe the relationship between HLA-B*57:01 and abacavir-induced hypersensitivity reactions.

Abacavir: used to treat HIV. However, abacavir-induced hypersensitivity can lead to SJS and organ injury.

• In 5-8% of patients, these symptoms occur during the first few weeks of therapy, and can become more severe if abacavir is continued.

Rechallenge of abacavir (restarting the med) may lead to severe reactions (e.g., renal failure). Thus, abacavir rechallenge is not appropriate.

HLA-B*57:01: the presence of this gene/allele confers high risk of abacavir hypersensitivity reaction (HSR).

Explain how the frequency of HLA-B*57:01 varies among populations.

Abacavir hypersensitivity rates among populations initiating treatment.

About 5–8% in Caucasians, 0–2% in Asians, 1% in Hispanics, and 0.5% in African Americans

Explain how HLA-B*57:01 testing can prevent abacavir-induced hypersensitivity reactions.

PG testing of HLA-B*57:01 can accurately predict patients who may be at risk for abacavir hypersensitivity.

In individuals with the HLA-B*57:01 variant allele ("HLA-B*57:01-positive"), abacavir is not recommended and should be considered only under exceptional circumstances.

• *57:01/*X and *57:01/*57:01 = positive; abacavir NOT recommended

• *X/*X = negative; use abacavir according to dosing guidelines

Interpret the FDA recommendation for HLA-B*57:01 testing before abacavir therapy

Screening for HLA-B*57:01 prior to initiation of abacavir is recommended by the DHHS Guidelines.

Screening for HLA-B*57:01 is recommended in the black box warning (Prescribing Information, FDA).

Apply HLA-B*57:01 test results to clinical decisions regarding abacavir.

Patients testing positive for the HLA-B*57:01 allele should NOT be prescribed abacavir.

Negative HLA-B*57:01 may still confer risk.