What is Pharmacogenomics?
Pharmacogenetics was coined in 1959, and focused on how a single gene affects how a patient responds to medication.
Pharmacogenomics (PGx) began being used after the Human Genome Project emerged in 2000, and focuses on how many genes interacting affect how you respond to medication.
Pharmacogenomics / pharmacogenetics are largely interchangeable terms.
Other factors that influence how you react to drugs/medication: the environment (your diet, what conditions you are exposed to), and clinical factors (age, severity of disease)
Precision Medicine and PGx
The idea behind precision medicine and PGx is to select the right dose of the right drug for the right patient at the right time.
Right now, when a doctor prescribes a drug, there are many options to choose from, which one the doctor chooses is largely due to her experience in practice on which drugs were effective for her patient population in the past. However, efficacy may vary widely and adverse affects are common and unpredictable. The doctor’s drug choice is also influenced to some degree by pharmaceutical reps and how well they market their drugs to doctors. What drug the patient ends up using is a trial and error process, the doctor prescribes something, the patient tries it out for a certain amount of time, and if the side effects are too great or if the medication isn’t effective, another prescription is given until the patients condition is being managed appropriately.
In the future, doctors will use genetics to guide drug and dose selection. “Patients with your genotype typically have a lower response”, “patients with your genotype typically experienced a higher rate of adverse reactions”, etc. Helps select more responsive patients.
The drug pathway:
- Pharmacokinetics (PK)- what your body does to the drug (digesting, metabolizing, excreting) (ADME)
- Absorption - passive, active, or co-transport
- Distribution - fat or water soluble
- Metabolism - broken down or modified (oxidation, methylation, sulfation, acetylation, glucuronidation)
- Elimination - renal excretion (to urine, liver excretion to bowel)
Genes that affect pharmacokinetics (PK):
metabolizing enzymes (CYPs, UGTs) and transporters - help the drug get in and out of the cell to where it is metabolized (ABCs, SLCs).
- Pharmacodynamics (PD) - what the drug does to the body Target - the molecules in the cell that the drug targets for its effect Mechanism of action
Genes that affect pharmacodynamics (PD):
GPCRs, kinases, ion channels, immune molecules.
Together, variation in the genes that affect PK and PD influence the efficacy and toxicity of a drug.
Some PGx Examples
- Thiopurines - alter dose or use alternate drug for poor metabolizers
- Clopidogrel - use alternate drug for ultra rapid metabolizers
- Codeine - alter dose or alternate drug for ultra rapid metabolizers
- Warfarin - alter dose based on PK and PD genes
- Single allele PGx - presence of one allele puts the patient at risk of ADRs
- Cancer PGx - drug targets genetic changes in tumors, PK genes
Purine analogs, 6-mercaptopurine, 6-thioguanine, azathioprine. This class of drugs is ssed to treat leukemias, inflammatory bowel disease, after transplant to immunosuppress the patient. Interferes with nucleic acid synthesis. Very severe side effect - fatal in some cases - myelosuppression, blood cells are not produced in bone marrow as they should be.
The gene TPMT is one of the very first examples of pharmacogenetics being used in the clinic. If you have the active form of TPMT, the drug gets incorporated into the DNA and has an effect.
Azathioprine gets broken down into 6-MP.
If you have TPMT, 6-MP gets converted into 6-methyl mercaptopurine, which is the inactive form of the drug.
If you don’t have TPMT, then most of the 6-MP gets converted into 6-thioguanine, which is the active form of the drug. (A small amount is converted into oxidized metabolites).
Here, we can see that TMPT levels drastically affects thioguanine levels.
If you have more TMPT, you have less thioguanines (you are deactivating most of the drug into 6-methyl mercaptopurine), and less efficacy against the disease.
If you have less TMPT, you have more thioguanines (you are converting too much azathioprine into thioguanine, the “average” dose given is actually resulting in twice the amount of medication being delivered), at high risk of severe bone marrow toxicity.
Phase I drug metabolizing enzymes Responsible for metabolizing a huge number of drugs CYP1, CYP2, CYP3 metabolize 90 percent of drugs used today
If you have an active form of the CYP enzyme, the drug is converted to an active form and the medicine works as intended. + wild type, no variant allele, normal metabolizer, 100 percent of enzyme function
If you have an inactive form of the CYP enzyme, the drug is not converted to an active form. You may have a build-up of the drug (toxicity) + intermediate metabolizer, 50 percent of enzyme function , 1 variant allele + poor metabolizer, 0 percent of enzyme function, 2 variant alleles
the drug may never be converted to an active form (the medicine doesn’t work). + (Ultra rapid metabolizer, 150 percent of enzyme function)
Anti platelet agent, trying to prevent clots 4 to 20 percent of people doesnt work poor metabolizers, box warning in 2010 not standard to be tested if you are a poor metabolizer
metabolized into morphine
cheap, widely used anti coagulant originally used as a rat poison INR - therapeutic range beginning, dangerous, not in therapeutic range other drugs on the market, more expensive, dont need to
HLA genes are part of the immune system If you have certain alleles, you never take certain medications because of severe reactions. Examples: + Allopurinol - HLA-B58:01 + Carbamazepine - HLA-B15:02 + Phenytoin - HLA-B58:01 + Abacavir - HLA-B57:01 Different allele frequencies mean different warnings in different populations
Genetics of your tumor Cetuximab A lot of oncology examples
PharmGKB [www.pharmgkb.org] FDA biomarker list - drug labels
Identify variation in drug response, reduce adverse events in
Challenges difficult RCT
Concerns: cost for genotyping (reimbursement), time delay to getting a response
Clinical adoption - integration into medical training, FDA drug labelling, publishing dosing guidelines
Thanks to Dr. Michelle Whirl-Carrillo PhD