PK, PD, Genomics Deck 2 Flashcards
Bioavailability
The fraction of administered drug
reaching systemic circulation in an
unchanged form that can produce
an effect
Bioavailability is
100% after IV administration
Oral bioavailability depends on
the amount absorbed and amount metabolized before reaching systemic circulation (first-pass metabolism)
First-Pass Metabolism
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?
bioavailability =
AUC oral/ AUC injected x 100
Routes that avoid first pass
transdermal im sub q sub lingual iv
Bioequivalence
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
Half-Life
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)
For most drugs, the rate of
elimination is NOT
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
First order elimination
the amount of the drug eliminated per unit time is proporational —- A constant % of drug is elimanted per unit time
One half life
Two half life’s
three half life’s
50%
25%
12.5%
Half-Life and Steady State
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
Steady State and Therapeutic Range
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
Dosing Frequency
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
Pharmacodynamic Changes in the Elderly
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)
Pharmacodynamic Changes in Pediatrics
• Response of drugs may be different due to immature receptors or
neurotransmitter systems
• Example: Antihistamines, barbiturates may cause paradoxical
excitement
Pharmacogenomics
- The study of how genes affect a person’s response to drugs
- Terms often used interchangeably
- Perhaps historically some differences
What can a pharmacogenomic test tell you?
pharmacogentics and pharmacogenomis are the same thing.
- 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
- 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
• 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?
• $$$
Genotype
– genetic make-up of an individual at a given locus
– Set of alleles an individual has for a trait
• E.g. CYP2D6 1/1
Phenotype
– the functional outcome of genotype(s)
– Trait that results from the individual’s set of alleles
• E.g. Extensive (normal) metabolizer
Polymorphism
genetic variation occurring in >1% of the
population
*1 reference sequence
*1 = ‘reference sequence’ • No identified functional change • “Extensive/normal” metabolizer phenotype • May not be the most common allele in every population
Other stars “*” represent
genetically distinct forms of a gene (allelic variants)
Phenocopy – variation in a
phenotype caused by
environmental exposure that mimics a genetically induced
phenotype
Example – drug
g inhibition may transiently ‘transform’ an
individual into a poor metabolizer
• Risperidone + paroxetine probably = poor CYP2D6 metabolism of
risperidone
Relevant enzymes:
CYP2D6, CYP2C19, CYP2C9, CYP3A5
Pharmacodynamic Variants
• 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)
FDA table of pharmacogenomic biomarkers in drug labeling - Pros
what drugs have PGx mentioned somewhere in labeling, where in labeling, sortable by drug, gene, and therapeutic area
FDA table of pharmacogenomic biomarkers in drug labeling - Limitations
does not assess actionability, based on data submitted as part of new drug applications
Clinical Relevance: Neuropsychiatic Drug Labeling
• 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
Carbamazepine Labeling - Equerto
Risk in asain population for Stevens Johnson Syndrome is 10 times higher than caucasion.
Source of ongoing debate
- 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
Resources for assessing evidence
• 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
Clinical Pharmacogenetics Implementation Consortium (CPIC)
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
Commercially available tests for psychiatry
• 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
Insurance Reimbursement – MN DHS
• 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.
• Factors supporting test utilization
- Many patients and providers want this information
* Strong PG-PK relationships for many medications
• Challenges to clinical implementation
- 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
PGx may augment
personalized decision making along with other
important clinical factors
