PK, PD, Genomics Deck 2

Question 1

Bioavailability

Answer 1

The fraction of administered drug
reaching systemic circulation in an
unchanged form that can produce
an effect

Question 2

Bioavailability is

Answer 2

100% after IV administration

Question 3

Oral bioavailability depends on

Answer 3

the
amount absorbed and amount
metabolized before reaching
systemic circulation (first-pass
metabolism)

Question 4

First-Pass Metabolism

Answer 4

Metabolism of a drug during
its passage from the site of
absorption into the systemic
circulation
• Extent of first-pass
metabolism differs among
drugs
Routes of administration that
avoid first-pass metabolism?

Question 5

bioavailability =

Answer 5

AUC oral/ AUC injected x 100

Question 6

Routes that avoid first pass

Answer 6

transdermal
im
sub q
sub lingual 
iv

Question 7

Bioequivalence

Answer 7

Occurs when two formulations of
the same drug have the same
bioavailability and rate of
absorption

Comparison of 2 or more products
with respect to their bioavailability

Example: Brand (Innovator) vs
generic product

Question 8

Half-Life

Answer 8

Half-Life (T1/2) = time necessary for the blood concentration of a drug to drop 50%
• Major determinant of:
- the duration of action after a single dose
- the time required to reach steady-state (or for the drug to be eliminated)

Question 9

For most drugs, the rate of

elimination is NOT

Answer 9

constant
over time, but varies with the
concentration
• Aka, for most drugs a constant
percent of drug is eliminated
per unit time rather than a
constant amount

Question 10

First order elimination

Answer 10

the amount of the drug eliminated per unit time is proporational —- A constant % of drug is elimanted per unit time

Question 11

One half life
Two half life’s
three half life’s

Answer 11

50%
25%
12.5%

Question 12

Half-Life and Steady State

Answer 12

Steady State means that at the same time after each identical dose, the blood
concentration should be nearly identical.
• Occurs after 4-5 half-lives

Question 13

Steady State and Therapeutic Range

Answer 13

Soon after dose given, concentration will reach a peak
• Right before next dose, concentration will reach a trough
• Goal is that when at steady-state, want peaks and troughs to be within the
therapeutic range
• So, the higher the therapeutic index (the bigger the therapeutic range) the
greater the peak-trough concentration variations can be

Question 14

Dosing Frequency

Answer 14

More frequent dosing with lower doses = smaller peak/trough
fluctuations
• Less frequent dosing with higher doses = larger peak/trough fluctuations
• When determining dosing frequency, pharmacodynamics just as
important as the half-life S

Question 15

Pharmacodynamic Changes in the Elderly

Answer 15

Brain atrophies, cells diminish and perfusion is decreased
• Increased sensitivity to drugs due to changes in receptor sensitivity
• Benzodiazepines, sedatives, narcotics, psychotropics
• Cholinergic neurons also diminish
• anticholinergic meds → mental status changes
• Ex: diphenhydramine
• Decreased adaptive homeostatic reflexes
• Increased risk of orthostatic hypotension due to blunted baroreceptor
reflexes
• ADRs that are simply bothersome to their younger counterparts can be severe
in the elderly (ex: alpha blockers causing orthostatic hypotension leading to a
fall & hip fracture)

Question 16

Pharmacodynamic Changes in Pediatrics

Answer 16

• Response of drugs may be different due to immature receptors or
neurotransmitter systems
• Example: Antihistamines, barbiturates may cause paradoxical
excitement

Question 17

Pharmacogenomics

Answer 17

• The study of how genes affect a person’s response to drugs
• Terms often used interchangeably
• Perhaps historically some differences

Question 18

What can a pharmacogenomic test tell you?

pharmacogentics and pharmacogenomis are the same thing.

Answer 18

• If you might be a fast or slow metabolizer of specific drugs
• Sensitivity to dose-related outcomes with specific drugs
• Side effects, response
• Some examples of hypersensitivity reactions
• Specific drugs – phenytoin, carbamazepine
• Possibly receptor sensitivity
• Related to side effects and response

Question 19

• If you might be a fast or slow metabolizer of specific drugs
• Sensitivity to dose-related outcomes with specific drugs
• Side effects, response
• Some examples of hypersensitivity reactions
• Specific drugs – phenytoin, carbamazepine
• Possibly receptor sensitivity
• Related to side effects and response

Answer 19

• Genetics is only one piece of the puzzle
• Other factors important: age, sex, body composition, liver function,
kidney function, etc
• Genes are not entirely deterministic
• Test results summarize ‘likelihood’ based on genetic information
• What if results conflict with personal experience?
• $$$

Question 20

Genotype

Answer 20

– genetic make-up of an individual at a given locus
– Set of alleles an individual has for a trait
• E.g. CYP2D6 1/1

Question 21

Phenotype

Answer 21

– the functional outcome of genotype(s)
– Trait that results from the individual’s set of alleles
• E.g. Extensive (normal) metabolizer

Question 22

Polymorphism

Answer 22

genetic variation occurring in >1% of the

population

Question 23

*1 reference sequence

Answer 23

*1 = ‘reference sequence’
• No identified functional
change
• “Extensive/normal”
metabolizer phenotype
• May not be the most
common allele in every
population

Question 24

Other stars “*” represent

Answer 24

genetically distinct forms of
a gene (allelic variants)

Question 25

Phenocopy – variation in a

Answer 25

phenotype caused by
environmental exposure that mimics a genetically induced
phenotype

Question 26

Example – drug

Answer 26

g inhibition may transiently ‘transform’ an
individual into a poor metabolizer
• Risperidone + paroxetine probably = poor CYP2D6 metabolism of
risperidone

Question 27

Relevant enzymes:

Answer 27

CYP2D6, CYP2C19, CYP2C9, CYP3A5

Question 28

Pharmacodynamic Variants

Answer 28

• Gene variants related to pharmacodynamics of neuropsychiatric drugs also
investigated
Examples: serotonin2A receptor (HTR2A), dopamine2
receptor (DRD2),
serotonin transporter (SLC6A4)
• Evidence exists to support hypotheses that these variants may influence
response or adverse effects to psychiatric meds
• Effect sizes small-mod and heterogeneous results across studies and
populations need to be resolved before widespread clinical application
• Not in product labeling or guidelines on how to use
• Association with disease risk, personality traits, or other psychiatric
phenotypes? – important to consider what results may mean to patient (and
relatives)

Question 29

FDA table of pharmacogenomic biomarkers in drug labeling - Pros

Answer 29

what drugs
have PGx
mentioned
somewhere in
labeling, where in
labeling, sortable
by drug, gene,
and therapeutic
area

Question 30

FDA table of pharmacogenomic biomarkers in drug labeling - Limitations

Answer 30

does
not assess
actionability,
based on data
submitted as part
of new drug
applications

Question 31

Clinical Relevance: Neuropsychiatic Drug Labeling

Answer 31

• Specificity and usefulness of pharmacogenomic language in product labeling highly
variable
• Provide varying levels of recommendations for what implications pharmacogenomic info
may have if available
- Some – specific recommendations based on metabolizer status
- Others – info regarding impact of metabolizer status on pharmacokinetics of a
drug or potential importance for drug interactions
• None mandate pharmacogenomic testing be performed

Question 32

Carbamazepine Labeling - Equerto

Answer 32

Risk in asain population for Stevens Johnson Syndrome is 10 times higher than caucasion.

Question 33

Source of ongoing debate

Answer 33

• Much debate about if/who/when/how
• Reality: Prescribers want more objective data to help with decisions, sometimes patient driven
• Just because testing available, does not equate to clinical utility
• Key: Knowing when to test and how to apply the results

Question 34

Resources for assessing evidence

Answer 34

• FDA
• Assesses pharmacogenomic data submitted as part of new drug applications
• Guideline/evidence grading groups
• Clinical Pharmacogenetics Implementation Consortium (CPIC)
• Pharmacogenomics Knowledgebase (PharmGKB)
• Guidelines designed to help clinicians understand HOW available genetic test results
should be used to optimize drug therapy.
• Not WHETHER tests should be ordered.
• Professional Organizations
• Task force groups assess evidence and publish manuscript or white paper
recommendations
• American Psychiatric Association
• American Association of Child and Adolescent Psychiatry
• International Society of Psychiatric Genetics

Question 35

Clinical Pharmacogenetics Implementation Consortium (CPIC)

Answer 35

Best evidence and consensus-based resource for HOW existing genetic information should be used
• Not WHETHER tests should be ordered
• Premise: existing genotyping will become more widespread
• Clinicians will be faced with having patients’ genotypes available even if they did not order test

Question 36

Commercially available tests for psychiatry

Answer 36

• Upwards of 20 companies >70 labs offer pharmacogenomic testing
through a healthcare practitioner
• Different companies/labs may test for different genes and variants
• “Combinatorial” clinical decision support results are common
• Combine both pharmacokinetic + pharmacodynamic genes
• Combinatorial algorithms are company-specific
• May provide recommendations about what to do
• Genotype/phenotype assignment and recommendations may differ
across commercial labs
• Clinical studies predominantly in depression

Question 37

Insurance Reimbursement – MN DHS

Answer 37

• Pharmacogenetic testing is covered when all the following conditions are met:
• Testing is required by the drug label
• The test will change the treatment course
• A drug trial is considered impractical due to safety or other factors prior to
genetic testing
• Pharmacogenetic panel tests for therapy selection, such as panel tests for
psychotropics, analgesics, or ADHD stimulant medications, are not covered.

Question 38

• Factors supporting test utilization

Answer 38

• Many patients and providers want this information

* Strong PG-PK relationships for many medications

Question 39

• Challenges to clinical implementation

Answer 39

• Studies lacking in patient populations where need is great
• Complex medication regimens
• Complicated diagnoses
• More prospective studies needed
• Clinical ‘decision support’ guided by commercial labs
• User friendly, but some details, assumptions, and generalizations differ from consensus reviews
• Many psychiatry test panels contain genes for which guidelines/labeling do not exist
• Reimbursement
• Regional differences
• Differences by diagnoses

Question 40

PGx may augment

Answer 40

personalized decision making along with other

important clinical factors