PK-PD models Flashcards
What is PD?
- Deals with the relationships between the drug concentration and the magnitude of pharmacological responses
What does PD represent?
Broad discipline to identify drug and system specific properties that regulate acute and long term biological responses to drugs
What is PD used for?
The context of therapeutic effects, whereas toxicology or toxicodynamics related to ADRs
What are example biomarkers/endpoints for PD for?
- To a presumed mechanistic effect
- To a potential or accepted surrogate
- To that full range of short term or long-term clinical effects related to either efficacy or safety
What are the different PD response to a drug?
- Rapid
- Delayed
- Stimulation or inhibition
- Functional adaptation
What are examples of rapid PD responses?
- Netutramitters
- Neuromuscula blockade
- Drug effects on electrical signals
What are examples of delayed PD responses?
- hormone effects
- mRNA effects
- Protein or enzyme changes
- Antibiotic effect
- Weight loss
- Bone density
- Smoking cessation
What are examples of functionally adapted PD responses?
- Desensitization of receptors
- Up or down regulation
- Precursor pool depletion
What happens once a drug reaches the effect site?
Interacts with receptors
What induces PD response?
Drug and receptor interaction
What is the classical theory of receptor occupancy?
Drug effect is proportional to the number of receptors occupied by drug and the maximal effect occurs when all receptors are occupied
What is the mathematical definition of the classic theory of receptor occupancy?
What are models?
Simplified descriptions of certain aspects of reality by mathmatical means
What are PD models?
Mathematical expressions based on classical receptor theory describing the intensity/magnitude of a pharmacological response of a drug as a function of its concentrations at the effect site
What is the purpose for PD model development?
To explain the complex mechanism of drug action
How are PD models categorized?
- Empirical
- Semi-mechanistic
- Mechanistic
What is the most frequently used PD model?
Empirical:
Emax and Sigmoid Emax
What are the characteristics of Emax?
- Describes the PD relationship over a wide range of drug concentrations
- Predicts the baseline and the maximum effects
What are the characteristics of sigmoid Emax?
- Able to describe an S shape pattern of effect curve by adjusting n values
- Predicts the baseline and the maximum effects
What does an Emax model assume?
- E is directly proportional to receptor occupancy (linear transduction)
- Cp rapidly equilibrates with the effect site, therefore, Cp drives PD
What is sigmoid Emax model?
Used when the effect curve exhibits an S shape pattern
What is another name for the sigmoid function?
Hill equation: where n is the Hill coefficient that affects the slope of the curve
Why is PD models important for determining dose-response relationship?
Help identify where PD and dose may be altered and thus dose adjustments are necessary
What are the disadvantages of PD models?
- Lack of correlation between Cp and concentration at effect site
- Difficulties in reliable and reproducible measurements of pharm effects
- Difficulties in quantifying direct pharm effects of a drug
- Complicated pharm effects
- Development of tolerance or sensitization after the prolonged exposure of a drug
- Disease induced PD alterations in receptor characteristics or effector-mechanisms
- Inter-indivudal or intra invidual variability in PD owing to genetic or environmental factors
What needs to be included in a complete model of drug response?
A PK model that describes the plasma concentration at any time after drug dose must be linked to a PD model that describes the response produced by any given concentration at site of action
What is most desirable approach to finding drug concentration?
Simultaneously measuring drug concentrations at the effect site (Ce) and its pharmacological response (R)
Not feasible to measure Ce
What can you say about drug concentration at ss?
Cp is assumed to be in equilibrium with Ce, unbound drug concentrations are the same in both the plasma and effect site
What is PD based on?
Cp
What can you say about drug concentration before ss or delay in drug distribution?
Cp and Ce are different
PD will take time to develop, and there will not be visible relationship between Cp and drug response (R)
What are PK parameters determine?
The plasma concentration at any time after the dose
What do the PD parameters determine?
The response to any concentration at the site of action
What happens id PK and PD are linked?
The response at any time after a dose can be estimated
What are some PD parameters?
Emax and EC50
What is the simplest approach to link PK and PD models?
Assume that the concentration at the site of action (Ce) is always in equilibrium with Cp (Simple PK/PD model)
When would other link models be used?
When the source of the delay is known
What are the types of PK/PD models?
simple, semi-mechanistic, mechanistic
Describe the mechanism of simple PK/PD models?
Describe the mechanism of mechanistic PK/PD models?
What are the characteristics of simple PK/PD models?
- Assume drug concentration at site of action is in equilibrium with the plasma at all times
- Response/effect in the PD model its driven by the plasma concetration
- Direct link exists between the PK and PD models
What is an example where there is a direct link between PK and PD?
Reduction BP by propranolol
What type of model is simple PK/PD?
empirical
What is the 1st disavantage of simple PK/PD models?
Does not accomodate time delays between receptor activation and the emergence of the response
How dot simple PK/PD models cause time delays?
- Sites of action are mostly extravascular, response lag behind Cp
- Time delays mask the relationships between concentration and response leading to hysteresis
What is hysteresis?
When response is plotted against concentration, different responses are seen at the same concentration
What causes hysteresis?
Caused by delayed distribution to the site of action, indirect drug action or a long transduction process
Why do we accommodate time delays?
To reveal the underlying direct relation between effect site concentration (Ce) and response
How can indirect link model affect simple PK/PD analysis?
Collapse the hysteresis to appropriately describe the time-delays causing the hysteresis
What are the disadvantages of simple PK/PD models?
- Don’t account intracellular signal transduction physiological processes from the time of drug-receptor interaction to PD response
- Don’t accommodate the concept of spare receptors
- Don’t accommodate time-dependent changes in the intensity of response while effect site concentrations remain constant
- Don’t adequately address drug tolerance and resistance
What is transduction?
Refers to the process and steps involved in the conversion of drug-receptor interaction into a measured biological response
What does mechanistic PK/PD models address?
The events that occur along the response chain subsequent to the receptor activation and the generation of the initial stimulus
How does mechanistic PK/PD incorporate receptor theory?
The model provides estimates of the drug specific parameters of efficacy and affinity
How does mechanistic differ from simple?
Drugs that act indirectly can be describbed
What are integrated/linked PK/PD?
Link dose-concentration relationships (PK) and concentration effect relationships (PD) thus facilitating the prediction of the time-course of drug effects of any dosing regimen
What are the methods of classifying integrated/linked pk/pd models?
- Depending on difference in the link between Cp and Ce
- Depending on how the response relates to Ce
- Depending on the strength of information used to establish the link between concentration and effect
- Depending on whether the response is time-dependent or independent
What is the models associated with the link between Cp and Ce?
- Direct link
- Indirect link
What is a direct link model?
When Cp is directly linked to Ce, therefore, Cp can serve as imput function in the PD component model
What is a indirect link model?
Required when there is a temporal dissociation between the time course of concentration and effect
What are the models associated with the response relating to Ce?
- Direct response
- Indirect response
What is direct response models?
The observed effect is determined by the Ce without time lag
What is indirect response model?
Are observed when temporal dissociation occurs between the time course of concentration of effect
What are the models associated with info to establish the link between concentration and effect?
- Soft link
- Hard link
What is soft link model?
When Cp and effect data are used to define the link function between PK and Pd
What is hard link model?
When PK and other data are used to predict PD
What are the models associated with time-dependent or independence?
- Time invariant
- TIme variant
What is time variant model?
The effect intensity is always secondary to the concentration and the PD parameters stay constant over time, most drugs follow this
What is the time variant model?
Time dependent changes on PD response resulting in change in the effect intensity without changes in the concentration at the effect site
What is the purpose of PK/PD modeling?
- estimate exposure measures (Cmax, AUC, Cmin)
- Examine correlation between PH endpoints ( therapeutic outcomes and adverse effects)
- Determine th safety and efficacy of drugs in the process of drug approval
- Estimate therapeutic window
- Determine appropriate dose
- Identify mechanism of action
