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