Pharmacogenomics Flashcards
Define pharmacogenomics
Study of genetics in drug response
Pharmacodynamics
- Is the therapeutic drug target present or not, or is it in some way changed?
- Do variants in non-target gene products, those that contribute to adverse effects?
Pharmacokinetics
- For which CYPs do variants exist?
- For which phase II enzymes do variants exist?
- For which transporters do variants exist?
Define genome
The whole of the genetic information of an organism found in the nucleus of eukaryotes
Define gene
A heritable factor that can control a specific characteristic
Define alleles
Specific forms of a gene differing by one or a few bases and occupying the dame gene locus
Most of action in pharmacogenomics is at the level of alleles
Define SNP
Single-nucleotide polymorphisms: An exchange of one nucleotide pair for another
- Coding regions can be synonymous (no change in amino acid production) or nonsynonymous (change in amino acid - may not have affect on protein function, but can)
- Noncoding regions
- Exchange is stable within a population (present in >1% of population)
Name some structural polymorphisms
- Gene deletion (ABCD => ACD)
- Inverted gene sequence (ABCD => ACBD)
- Copy number variant/amplification (ABCD => AAAAABCD)
- Insertion (ABCD => ABACD)
Describe how SNPs can affect clinical outcome
- About 1 million SNPs, most won’t change pharmacokinetics/drug response
How is pharmacogenomics incorporated into drug labeling?
Appears on ~150 FDA-approved drug labels
- Genetic testing required
- Genetic testing recommended
- Actionable PGx: should consider genetic testing, significant evidence for it
- Informative: conjecture, not enough evidence
Which CYPs have meaningful polymorphisms?
CYP2C9, CYP2C19, ***CYP2D6
What is the difference between genotype and phenotype?
Genotype: how genes are written
Phenotype: how genes are expressed
Describe how genotype affects phenotypes of CYP2D6
- Ultra metabolism (UM): >2 functional alleles (see more of metabolite)
- Extensive metabolism (EM): 1-2 normal alleles
- Intermediate metabolism (IM): 2 reduced-function or 1 null allele & a reduced-function allele
- Poor metabolism (PM): 2 null alleles (no functional CYP2D6)
Discuss the most important CYP2D6 alleles
- Null alleles: cause most of PM phenotypes - *3 frameshift, *4 splice variant, *5 gene deletion, *6 frameshift
- Alleles responsible for reduced function, hence IM phenotypes: *10, *17, *41
- Alleles responsible for amplified activity, hence UM phenotypes: *1xN, *2xN
How does a UM of CYP2D6 affect metabolism of codeine?
- Codeine is a weak analgesic
- Normally, mostly metabolized by CYP3A4, small amount by CYP2D6 into morphine
- If a drug that irreversibly inhibits CYP3A4 is present, more will be directed toward CYP2D6 for metabolism more metabolized bc UM, more morphine made, phase II reactions cannot handle amount of morphine, CNS/respiratory depression
What is the bottom line for metabolism of a drug be different CYP2D6 phenotypes?
UM: small amount of inactive prodrug => large amount of active metabolite
- Increased in Cmax &/ AUC of active entity relative to other patients
PM: lots of inactive prodrug needed => small amount of active metabolism
- Decrease in Cmax &/ AUC of active entity relative to other patients
What medications have required or recommended genetic testing for CYP variations prior to initiation of drug therapy?
Required: - Pimozide = Cyp2D6 - Tetrabenzine = CYP2D6 Recommended: - Clopidogrel = CYP2C19 - Dextromethorphan + quinidine = CYP2D6 Actionable: Usually cytochromes, occasionally phase II enzymes
Describe PGx considerations for warfarin
- Warfarin inhibits enzyme VKORC1 - less of coagulation effect
- Duality of pharmacodynamics and kinetics!*
- Diminished activity of CYP2C9 noted for 2 common polymorphic variants, *2 & *3 (less enzyme activity, less eliminated - PK)
- Diminished level VKORC1 noted for one common polymorphic variant, *2, or “A” abnormal instead of “G” good/normal (less therapeutic target - PD)
What is the basis for requirement of genetic testing?
Pharmacokinetic level:
- Need to anticipate polymorphism-based pharmacokinetic changes that definitely undercut efficacy or cause serious adverse effects
Pharmacodynamic level:
- Need to determine whether a therapeutic target exists (relates mostly to cancer pts to see if pt has therapeutic target for certain chemotherapeutic agents)
- Need to anticipate polymorphisms unrelated to therapeutic target (or pharmacokinetics) that cause or correlate with serious adverse effects (life-threatening skin rashes caused by carbamazepine associated with HLAB*1502, G6PD deficiency treated with rasburicase, increased risk for severe hemolysis)
What is carbamazapine’s relation to HLA-B allelic variant 1502? What is the common population with this allelic variation?
- HLA-B is a complex that is brought to cell surface and presented to cytotoxic T cell when binds to something out of place like a virus
- HLA-B*1502 binds carbamazepine as if it were a dangerous peptide, presents it to cytotoxic T cell, is destroyed => rash
- Asian population*
What medications have required or recommended genetic testing for HLA variations prior to initiation of drug therapy?
Required:
- Carbamazepine = HLA-B*1502 in Asians
Recommended:
- Acabavir = HLA-B*1502 in Asians
Effects of G6PD deficiency
- Glutathione is a detoxifier in liver, antioxidative purpose in RBCs
- If G6PD deficiency, more sensitive to oxidizing potential & destruction of RBCs
What medication has required genetic testing for G6PD deficiency prior to initiation of drug therapy?
Required:
- Rasburicase for Africans/Mediterraneans
Describe NAVAGATE
- Necessary
- Alternatives
- Validated test (how do you collect?)
- Appropriate turnaround time
- Good evidence (in regards to what to do with result: increase/decreased dose, increase monitoring?)
- Acceptance (pt/provider)
- Test reimbursement/payment (how will pt pay?)
- Evaluate results & document (how will be recorded in chart?)
How is clopidogrel affected by PGx?
- Clopidogrel is a prodrug
- CYP2C19 most important metabolic enzyme for metabolic activation
- CYP2C19 loss-of-function alleles are associated with a) decreased levels of clopidogrel active metabolite and b) increased CV outcomes in ACS/PCI pts (won’t be effective in regards to AC)
- Black-box warning regarding CYP2C19 PMs: advised genetic testing & other antiplatelets/alternative dosing for PMs
What are the ACCF and AHA recommendations and NIH recommendations regarding the clopidogrel black box warning?
ACCF & AHA
- Recognize impact of CYP2C19 polymorphisms
- Evidence insufficient to recommend routine genetic testing - warranted in pts with mod/high risk of poor outcomes
NIH, 2 options
- Genotype all pts who undergo PCI
- Genotype only pts who are at mod/high risk for poor outcomes
