Pharmacogenomics

Question 1

Why is Genome sequencing cheaper now? Why is this beneficial?

Answer 1

Next-generation sequencing (NGS), became available and costs suddenly decreased.

The rapidly falling cost of genome sequencing, is allowing all new drug discovery to include a genome component in clinical development. This will help to identify if there are patient groups who do not respond or respond with better efficacy dependent on their genomes. If so , then patients could be selected for treatment with the drug following a gene sequencing test

Question 2

Give an example of a Genome sequencing device?

Answer 2

Oxford Nanopore

Question 3

Why is Pharmacogenetics important?

Answer 3

Uses genetics to optimize drug therapies, maximize drug efficacy, and minimize adverse drug reactions in patients.

Question 4

Define Pharmacogenetics

Answer 4

The study of genetic causes of individual variations in drug response

• [ ] There is emphasis on studying individual patients
• What is the polymorphism in this patient?
• What are the individual consequences?
• We need a clear black and white answer → To give precise prescribing advice

Question 5

Define Pharmacogenomics

Answer 5

Broadly involves genome-wide analysis of genetic determinants of drug efficacy and toxicity.

Question 6

Human Variability is dependent on…

Answer 6

Genes + Environment

Question 7

What are the types of genomic variability?

Answer 7

1. Germline Mutations→ Affect Pharmacokinetics & Pharmacodynamics of medicines
   germ cells that are the egg and sperm cells and are passed on
2. Somatic Mutations→ Lead to Tumor heterogeneity & Oncology treatments
   An alteration in DNA that occurs after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children.

Question 8

What are the common gene based effects?/ how do genes affect the drug profile?

Answer 8

1. Pharmacokinetics:
   
   • Polymorphisms (variance in the DNA sequence ) of any genes that regulate ADME elements
   • Drug transporters
   • Metabolizing enzymes - CYPs
   💡 No single enzyme determines the total pharmacokinetics of any one medication.
   All about optimizing dosing, this used to be entirely empirical (low dose prescribed until efficacy). With Genetics there is an opportunity now to start to predict this for each patient - saving time & increasing prospects for patients.
2. Pharmacodynamics :
   
   • Polymorphisms in drug target (e.g. histamine receptors- polymorphisms of histamine will effect the drug affinity etc.) → Few examples to date because drug binding sites are often the same binding sites for the natural ligand (conserved via evolution). If you have significant mutations in these binding sites they can be lethal.
   • Target expression levels
   • Pathways affecting the target → There are more examples here.

Question 9

How can we improve patient’s drug treatments using pharmacogenomic input?

Question 10

Give examples of drugs metabolized by CYP2D6?

Answer 10

Amitriptyline, Codeine & Tamoxifen

Question 11

Why is CYP2D6 important?

Answer 11

• The ROA for many drugs
• More than 100 polymorphisms
• Significant numbers of human population have these polymorphisms which results in significant changes in enzyme function → The genotype has an impact on the phenotype

Question 12

Give 3 clinical actions used when making changes to patient therapy?

Answer 12

1. Dose adjustment → We need evidence that the dose adjustment is effective. Usually therapeutic drug monitoring is advised.
2. Alternative therapy → If a drug is inactive or toxic to particular genotypes
3. Not sure of the impact → Genotype has an impact but action as a consequence is unclear.