Precision Medicine & Pharmacogenomics

• PGx is pharmacogenomics

Objectives

• Understand problems with current drug therapy
• Understand precision medicine
• What factors alter drug response
• Define pharmacogenetics and pharmacogenomics
• Describe the relations between pharmacogenetics (PG), pharmacokinetics (PK) and pharmacodynamics (PD)
• Describe genomic biomarkers

Problems with Rx Drugs

• Everyone is different
• Currently, most are treated in the same way with no consideration for individual differences

Difference in Drug Response

• Alzheimer's has an efficacy rate of 30%
• Analgesics (Cox-2) has an efficacy rate of 80%
• Asthma has an efficacy rate of 60%
• Cardiac arrhythmias has an efficacy rate of 60%
• Depression (SSRI) has an efficacy rate of 62%
• Diabetes has an efficacy rate of 57%
• HCV has an efficacy rate of 47%
• Incontinence has an efficacy rate of 40%
• Migraine (acute) has an efficacy rate of 52%
• Migraine (prophylaxis) has an efficacy rate of 50%
• Oncology has an efficacy rate of 25%
• Osteoporosis has an efficacy rate of 48%
• Rheumatoid arthritis has an efficacy rate of 50%
• Schizophrenia has an efficacy rate of 60%

Difference in Adverse Drug Reactions (ADRs)

• Over 2 million serious ADRs yearly
• About 100,000 deaths yearly are attributed to adverse drug reactions (4th leading cause of death)
• ADRs kill more people each year than pneumonia, diabetes, Alzheimer's, suicide, homicide, septicemia, kidney disease, or liver disease
• Approximately 20% of drug candidates are terminated during development
• Approved drugs can be withdrawn from the market

Problems with Rx Drugs

• Drug response rate and adverse drug reactions (ADRs) are highly variable

Consequences of "One Size Fits All"

• Includes time spent going to and from the doctor
• Money spent on ineffective medications
• Death/sickness due to adverse drug reactions

Precision Medicine

• Formerly called "Personalized" or "Individualized medicine"
• Precision medicine is a contrast to "one-size-fits-all"
• It focuses on getting the right dose of the right drug to the right patient at the right time
• A goal is to increase efficacy and decreasing ADR

Precision Medicine Definition

• Is an emerging approach for disease treatment and prevention
• Takes into account individual variability in genes, environment, and lifestyle for each person

Factors for different drug response and ADRs

• Disease, development, environment, genetics, organ function, drugs all play a role in absorption, distribution, receptor interaction, biotransformation and excretion
• Largely genetically controlled

What is Pharmacogenomics?

• Pharma means drug or medicine
• Genomics means the study of genes
• Pharmacogenomics is personalized medicine tailored to your genes
• The terms pharmacogenomics and pharmacogenetics are used interchangeably
• Pharmacogenetics considers one or at most a few genes of interest
• Pharmacogenomics considers the entire genome

Two Important Concepts

• Pharmacokinetics is the study of what the body does to a drug
• Pharmacodynamics is the study of what a drug does to the body

Impact of Pharmacogenomics on Pharmacokinetics and Pharmacodynamics

• Genes and variants can affect clinical outcome, pharmacodynamics and drug responses, pharmacokinetics, molecular and cellular functional assays, and genotype

Example: Isoniazid PK

• Plasma elimination half-life values vary for drugs used in medical therapy
• Intersubject variability in PK is common for many drugs

Isoniazid PK/PG

• PK variants are due to genetic variants in N-Acetyltransferase 2 (NAT2)
• Slow acetylators have a higher risk of drug-induced toxicity
• Rapid acetylators have lower treatment success rates
• Dose adjustment for slow acetylators should be reduced
• Dose adjustment for rapid acetylators should be increased

Genomic (PGx) Biomarkers

• A measurable DNA, RNA and/or protein that is an indicator of drug response
• It's obtained from PGx testing and can be used to identify non-responders or toxic-responders, and determine the treatment plan

PGx Biomarkers are used to determine or predict

• An individual's response to a certain drug based on variations in their genes encoding for:
• Drug metabolizing enzymes (PK)
• Drug transporters (PK)
• Drug targets (PD)

History of PGx

• 1953: Watson and Crick describe DNA's double helix
• 1956: Investigators discover a genetic link to hemolytic reactions to primaquine
• 1957: Motulsky proposes that inheritance might explain individual differences in the efficacy of drugs and in the occurrence of adverse drug reactions
• 1959: Fredrich Vogel introduces the term "pharmacogenetics"
• 2003: Human Genome Project is completed

In Use Today

• Fast growing field
• More and more PGx biomarkers has been used in clinical practice, e.g., Cytochrome P450 (CYP) family of enzymes, Enzyme thiopurine methyltransferase (TPMT), Oncology biomarker HER2, etc
• FDA pursuing pharmacogenomic policy initiatives
• Industry using pharmacogenomic data for drug development

Pharmacogenomics and Pharmacists

• Pharmacists are important in the education, implementation, and research of pharmacogenomics
• Pharmacists understand the concept of PGx
• Pharmacists are able to order PGx tests, report and interpret the test results for the patients
• Pharmacists are uniquely positioned to lead inter-professional efforts to use PGx
• Some advanced pharmacist functions in applying clinical PGx may require specialized education, training, or experience

Explore precision medicine's central aims, pharmacogenomics' role, and causes of adverse drug reactions. Understand how pharmacokinetics and pharmacodynamics relate to pharmacogenomics, distinguishing pharmacogenetics from pharmacogenomics. Learn about the consequences of the 'one-size-fits-all' approach and factors influencing drug response variability.