PHARMACOGENOMICS AND PRECISION MEDICINE
Mahesh S. Trivedi, Pranoti Sharma, A.K. Patil
Pharmacogenomics is a field of study that combines pharmacology and genomics to understand how an individual’s genetic makeup influences their response to drugs. It involves analyzing the genetic variations (polymorphisms) that can affect drug metabolism, efficacy, and potential adverse reactions. Sometimes chemical changes can make the drugs more—or less—active in the body. The goal of pharmacogenomics is to personalize medication and treatment plans to optimize therapeutic outcomes while minimizing side effects. Its long-term goal is to help doctors select the drugs and doses best suited for each person. It is part of the field of precision medicine, which aims to treat each patient individually.
Key aspects of pharmacogenomics include:
- Genetic Variations: Genes are instructions, written in DNA, for building protein molecules. Individuals can have genetic variations that impact the way their bodies metabolize drugs. Each version has a slightly different DNA sequence. These variations can affect enzymes, transporters, receptors, and other components involved in drug interactions within the body.
- Drug Metabolism: Scientists know that certain proteins affect how drugs are metabolized in the body. Pharmacogenomics helps identify genetic variations that influence the metabolism of drugs. These proteins include liver enzymes like cytochrome P450 (CYP) enzymes. The activity of these enzymes plays a crucial role in drug metabolism.
- Efficacy and Safety: By studying an individual’s genetic profile, healthcare providers can predict which drugs are likely to be most effective and safe for that person. This can help avoid adverse reactions and increase treatment success rates. Even small differences in the genes for these drug biotransforming enzymes can have a big impact on a drug’s safety or effectiveness.
- Dosing Optimization: Pharmacogenomic data can guide healthcare professionals in determining the optimal drug dosage for a patient based on their genetic characteristics. This personalized approach can reduce the risk of underdosing or overdosing.
- Drug Selection: Physicians can choose the most suitable drug or treatment regimen based on a patient’s genetic information. This is particularly valuable in fields like oncology, where targeted therapies are increasingly used. Here are some examples of pharmacogenomic testing in cancer care:
- Colorectal cancer-Irinotecan (Camptosar) is a type of chemotherapy. Commonly used by clinicians to treat colon cancer. In some people, genetic variations cause a scarcity of the UGT1A1 enzyme. This enzyme is liable for metabolizing irinotecan. With a UGT1A1 deficiency, higher levels of irinotecan remain in the body. This may lead to severe and potentially life-threatening side effects. The risk is greater with higher doses of the drug. Doctors may use a pharmacogenomic test called the UGT1A1 test. It shows which people have this genetic variation. Then, the doctor may prescribe a lower dose of irinotecan. Often, the lower dose is effective for these people.
- Acute lymphoblastic leukemia (ALL). Doctors use pharmacogenomic testing for children with ALL. About 10% of people have genetic variations in an enzyme called thiopurine methyltransferase (TPMT). TPMT is responsible for metabolizing chemotherapy for ALL. Children with lower TPMT levels receive lower chemotherapy doses. This helps in preventing severe side effects in Children with lower TPMT levels.
- Other cancer types.Fluorouracil (5-FU) is a type of chemotherapy. It is used to treat several types of cancer including colorectal, breast, stomach, and pancreatic cancers. A genetic variation in some people causes lower levels of the enzyme called dihydropyrimidine dehydrogenase (DPD). DPD helps the body metabolize fluorouracil. Doctors may use a pharmacogenomic test to find this variation. If found, a lower fluorouracil dose helps prevent serious side effects.
- Adverse Event Prediction: Genetic markers can be used to identify patients who may be at higher risk for adverse drug reactions. Adjustments to medication plans can then be made to minimize these risks. If scientists can identify genes that cause serious side effects, clinicians could prescribe those drugs only to people who do not have those genes. This would allow some individuals to receive potentially lifesaving medicines that otherwise might be banned because they pose a risk for other people.
- Drug Development: Pharmaceutical companies use pharmacogenomics in drug development to identify potential genetic markers for drug response or resistance. This can aid in selecting patient populations for clinical trials and developing more effective therapies. Drug companies are also using pharmacogenomics to develop and market medicines for people with specific genetic profiles. By studying a drug only in people likely to benefit from it, drug companies might be able to speed up the drug’s development and maximize its therapeutic benefit. For example, Cystic fibrosis is caused by mutations in the CFTRgene which affect the CFTR protein. The CFTR protein forms a channel, which acts as a passageway to move particles across the cells in your body. For most people the protein is made correctly, and the channel can open and close. Some mutations that cause cystic fibrosis result in a channel that is closed. The drug ivacaftor acts on this type of mutation by forcing the channel open. Ivacaftor would not be expected to work for people with cystic fibrosis whose mutations cause the channel not to be made at all.
- Ethical Considerations: Pharmacogenomics raises ethical concerns related to privacy, informed consent, and the potential for genetic discrimination. Ensuring patient autonomy and confidentiality is crucial in implementing pharmacogenomic testing.
In practice, pharmacogenomics is becoming increasingly relevant in healthcare, particularly in areas like cancer treatment, psychiatry, and cardiology, where individual responses to medications can vary widely. It enables healthcare providers to tailor treatment plans to the specific genetic makeup of each patient, leading to more effective and safer healthcare interventions. It may improve patient safety. Severe drug reactions cause more than an estimated 120,000 hospitalizations each year. Pharmacogenomics may prevent these by identifying patients at risk. It may also improve health care costs and efficiency along with finding appropriate medications and doses more quickly.
However, it’s important to note that while pharmacogenomics holds great promise, it is not the sole determinant of drug response, and other factors such as age, diet, and drug interactions should also be considered in clinical decision-making. Pharmacogenomics is expensive and access to certain tests may be limited in some places. In some countries laws prohibit discrimination based on genetic information.
