Pharmacogenetics: Personalized Medicine

Pharmacogenetics

• Personalized medicine to tailor the drugs and treatment to individuals based on their genetic code
• Figuring out the correct dose of a medicine may be as simple as 'taking our temperature'
• It is the study of how genes affect a person's response to drugs and controlled variations in drug response.

Why Pharmacogenetics?

• Needed for the management of chronic diseases, especially diseases treated with drugs.
• In primary care, polypharmacy is rampant which increases healthcare utilization and costs.
• Polypharmacy increases healthcare costs by around 30% in recent years.
• Reduced adherence to drug therapy regimens usually follows adverse drug reactions and polypharmacy.
• Adverse Drug Reactions (ADRs) represent major challenges for polypharmacy patients.
• At-risk patients with multiple conditions are a major concern.
• Individuals respond differently to drugs
• Clinically significant drug-drug and drug-gene interactions were observed and reported
• Acetylation status checks can be early signals for individual difference responses to drugs.
• Different alleles and metabolizing outcomes lead to pharmacogenetics

Pharmacogenomics (PGx)

• Discipline for genome-wide assessment of how individual genes, alone or in combination with other genes, impacts drug treatment.
• Broader study than pharmacogenetics on how multiple genes influence drug response, through technologies like whole-genome sequencing.
• PGx combines pharmacology (uses, effects, and modes of action of drugs) and genomics (structure, function, evolution, and genome mapping) to develop tailored, safe medication regimens.
• PGx aids the prediction and stratification of:
  • Who may benefit from a medication
  • Who may not respond at all
  • Who may experience adverse reactions
• Due to possible variation from the reference genome, clinical use and application of pharmacogenomic testing is limited.
  • This is largely due to a lack of evidence supporting clinical utility and cost effectiveness.

Pharmacogenetics vs. Pharmacogenomics

• Pharmacogenetics focuses on specific genes like CYP2D6 and CYP3A4.
• Pharmacogenomics considers the entire genome and interactions between multiple genes.
• Pharmacokinetics determine drug response, including disposition, safety, tolerability, and efficacy.
• Pharmacogenomics employs tools for surveying the entire genome to assess multigenic determinants of drug response.

Genetic Variants

• A variant is a difference in an individual's genome from the reference genome
• Single nucleotide variants (SNVs) involve the change of one base.
• Insertions or deletions (Indels) can change the reading frame or add/delete a codon.

Types of Genetic Variants

• Polymorphism is a variation in the DNA sequence with an allele frequency of 1% or greater in a population.
• Two major types of sequence variation are:
• Single Nucleotide Polymorphisms (SNPs)
• Insertions/Deletions (indels).
• Indels are less frequent in the genome, especially in coding regions.
• A single nucleotide polymorphism (SNP) is a variation in a single nucleotide at a specific position in the genome, present to some degree within a population (e.g., >1%).

Genetic Variation's Affects on Drugs

• Genetic polymorphisms can affect both pharmacokinetics (drug absorption, distribution, metabolism, and excretion) and pharmacodynamics (drug effects on receptors, ion channels, and enzymes).
• Polymorphism is the presence of two or more variant forms of a specific DNA sequence among different individuals or populations.
• "One-size-fits-all" drugs only work for about 60% of the population, 40% have an increased risk of adverse drug reactions (ADR) due to how their genes work.

Importance of Pharmacogenetics

• Pharmacogenetics studies genetic bases for variability in drug response.
• Pharmacogenomics uses genetic information to guide drug choice and dose on an individual basis.

Pharmacogenetic Phenotypes

• Genetic variations affecting drug response can be divided into three categories:
• Variations affecting pharmacokinetics
• Variations affecting drug receptor/target
• Disease-modifying variations

Pharmacokinetics

• Phase 1 biotransformation involves oxidation, hydrolysis, and reduction, with the use of CYP450s enzymes.
• Phase 2 involves synthesis and conjugation.
• Metabolites from both phases are excreted.
• CYP2D6 deficiencies can have the following consequences:
• Phenotypic consequences
• Increased risk of toxicity from antidepressants
• Lack of analgesic effect from codeine
• Deficient ultra-rapid metabolizers are associated with extremely rapid clearance and less effective antidepressants.
• Debrisoquin-Sparteine oxidation polymorphism consists of the following population variances:
• Poor metabolizers
• Intermediate metabolizers
• Extensive metabolizers
• Ultrarapid metabolizers

CYP2C19 Polymorphism

• Aromatic hydroxylation of anticonvulsant mephenytoin takes place
• Extensive metabolizers:
• (S)-mephenytoin is extensively hydroxylated by CYP2C19 before glucuronidation and rapid excretion in the urine.
• (R)-mephenytoin is slowly N-demethylated to nirvanol, an active metabolite.
• Poor metabolizers:
• Lack of stereospecific (S)-mephenytoin hydroxylase activity, so both (S)- and (R)-mephenytoin enantiomers are N-demethylated to nirvanol, accumulating at high concentrations.
• Increase the therapeutic efficacy of omeprazole in gastric ulcer.

Other Enzymes

• UGT polymorphism (Uridine 5'-diphospho-glucuronosyltransferase) can cause toxic side effects due to impaired drug conjugation/elimination (e.g., anticancer drug irinotecan).
• TPMT (thiopurine S-methyltransferase) gene polymorphism reduces the detoxification of thiopurines, increasing the risk of drug-induced fatal hematopoietic toxicity.
• Alterations of drug acetylation rate in different populations can affect N-acetyltransferase (NAT2) genes.
  • Slow acetylators: Peripheral neuropathy
  • Fast acetylators: Hepatotoxicity linked to Isoniazid
• Suxamethonium and pseudocholinesterase deficiency causes the following:
  • Mutation lead to abnormal cholinesterase.
    • Individuals are unable to inactivate Suxamethonium rapidly and experience prolonged neuro-muscular blockade.
    • Frequency: 1/3000

Genetic Polymorphisms & Drug Type

• Variations in the following result in adverse effects Inactivation of MTFHR leads to GI Toxicity from Methotrexate
• Serotonin receptor polymorphism reduces responsiveness to Depression
• Beta recepor polymorphism affects responsiveness to Asthma
• Polymorphism in HMG-CoA Reductase affects Statins
• Polymorphism in Ion Channels affects cardiac function of drugs

Polymorphism Modifiers

• Methylenetetrahydrofolate reductase (MTHFR) polymorphism links to homocysteinemia, which then affects thrombosis risk.
• Polymorphisms not directly affecting PK or PD may modify thrombosis risk with prothrombotic drugs like glucocorticoids, estrogens, and asparaginase.
• Polymorphisms in ion channels increase cardiac arrhythmias risk, especially with QT-prolonging drugs.
• For example: Human ether-a-go-go-related gene (HERG) can cause channel issues KvLQT1- a voltage-gated potassium channel with risk cardiac arrhythmias Mink encodes to the germinal center kinase (GCK) family

Various Types of Tests

• HLA gene tests:
• Abacavir & HLAB*5701
• Anticonvulsants & HLAB*1502
• Clozapine & HLA-DQ 1*0201
• Drug metabolism related gene tests:
  • Thiopurine & TPMT
  • 5-Fluorouracil (5-FU) & DPYD
  • Tomoxifan & CYP2D6
  • Irinotecan & UGT1A1*28
• Drug target related gene test:
• Trastuzumab & HER2
• Dasatinib, Imatinib & BCR-ABL 1
• Combined (metabolism & target) gene test:
• Warfarin & CYP2C9 + VKORC 1 GENOTYPING

Amplich IP

• Determines the patient's genotype for CYP450 enzymes 2D6 and 2C19.
• The Amplichip CYP450 test was FDA approved on Dec 24, 2004, and it is the first FDA approved pharmacogenetic test.

Pharmacogenetics & Drug Development

• It may identify new targets and assess genes whose expression differentiate inflammatory processes.
• Compounds can be identified that change expression of genes responsible for inflammatory processes.
• These can be used as starting points for anti-inflammatory drug development.
• Subsets of patients can be identified who may respond well to an agent or have low likelihood of responding, testing the drugs accordingly
• Identifying the subpopulation for higher risk of ADR
• Pharmacogenetic data can be submitted to FDA during IND & NDA application

Pharmacogenetics challenges

• Despite considerable research activity, pharmacogenetics is not yet widely utilized in clinical practice.
• There is resistance to acceptance or there is unfamiliarity by clinician due to principles of genetics and adjusting doses on pharmacogenetic data.
• Genetic discrimination occurs if people are treated unfairly because of differences in their DNA that increase rates of getting certain illnesses
• A health insurer might refuse coverage based on DNA
• Employers also could use DNA information

Advantages of Pharmacogenomics

• Predict a patient's response to drugs
• Develop "customized" prescriptions
• Minimize or eliminate adverse events
• Improve efficacy and patient compliance
• Improve rational drug development
• The test needs to be conducted only once during the lifetime
• Improve the accuracy of determining appropriate drug dosages
• Screen and monitor certain diseases
• Develop more powerful, safer vaccines
• Allow improvements in drug discovery and development

Barriers to Pharmacogenomics

• Complexity of finding the gene variations that affect drug response Millions of SNPs must be identified and analyzed to determine their involvement in drug response
• Confidentiality, privacy and the use and storage of genetic information must be secured
• Education of the general public and Healthcare Providers is needed
  • Complicates the process of prescribing drugs and dispensing
  • Requires physicians to determine which medicine is best according to test
• Disincentives for drug companies to make multiple pharmacogenomic products
  • Most companies have been successful with "one size fits all" and only selling that

Pharmacogenomics and Personalized Medicine

• Pharmacogenomics is in the early stages of development
• Human Genomics offers hope on the "Personalized Medicine."
• Reality of the added complexity & need for interpretation of results to individualized dosing has been ignored
• The wide prescription of prevention of thromboembolic events is known as Warifarin
  • Narrow therapeutic index
  • 20-fold individual dose variation

Dosing and Bleed Effects

• Gene variation leads to increased expression of CYP2C9 and VKORC1
• Interaction with amiodarone due to inhibition of CYP2C9; amiodarone increases level of warfarin, and bleeding events
• Not effective Under dosing leads to thromboembolic events and Overdosing can cause Bleed events

Pharmacogenetic Profiling

• P3 Personalized Pharmacogenetic Profile categorizes patients into several risk subtypes based on the same diagnosis P3-normal is treated with a conventional dose
• P3-Moderate Risk is treated with alternative drugs or reduced dosage P3-Elevated Risk is treated with alternative drugs or reduced dosage

Clinical Use Tips

• Genetic variants alter drug metabolism, affecting drug concentration, efficacy, and toxicity.
• Enzyme activity (CYP2C9, CYP2D6), transporter function (ABCB1), and target receptor affinity are variations that can impact variants
• Reduced warfarin metabolism leads to increased bleeding risks

Clinical Implications

• Personalized medicine aims to tailor treatment to individual genetic profiles.
• Optimized dosing to reduce toxicity and improve efficacy.
• Alternative medication selection to avoid adverse reactions.
• Improved patient outcomes by decreasing negative effects and enhancing treatments.
• Adjustment of Warfarin dose based on CYP2C9
• Avoid Abacavir in HLA-B*5701 in positive patients to avoid ADR.

Talking to paitents

• Explain the purpose and benefits of testing.
• Impact the discussion on a case by case basis.
• Emphasize individualized care
• Talk and Address the concerns and genetic privacy of results

Case Studies

• Reduce warfarin dose by 20-30% due to decreased CYP2C9 enzyme activity for 65-year-old heterogenous patients.
• Use ticagrelor or prasugrel when treating 50 year old patients that show reduced clopidogrel efficacy.
• If decreased with codeine aternatives should be used instead.
• For patents with positive HLA B*5701 test.
• Hypersensitivity can be avoided with a test.
• Clinomics combines genetic information with clinical data for personalized medicine.
• There are important ethical and legal considerations in pharmacogenomics, including privacy concerns and informed consent.