Populational PKPD Analysis Flashcards
The ______ used to measure drug concentrations also has variability.
Assays.
Variability is not a major concern for what drugs.
Those that don’t have a narrow therapeutic window.
Factors affecting PK/PD are known as ____________
Covariates.
This form of PK analysis focuses on:
1. Homogenous Population
2. Single Dose Studies
3. Small Study Groups
4. Intensive Sampling
Traditional PK analysis
This form of PK analysis focuses on:
1. Phase II/III Trials
2. Heterogenous patient population
3. Lack of simple experimental paradigm
4. Sparse sampling strategies
5. Complicated and time-intensive analysis.
Routine Clinical Trials.
Quantitative relationship between parameter values and co-variates.
Covariate Model of Populational Analysis
Variability of parameter values across populations of patients.
Statistical Model of Populational Analysis.
Analyzes mean PK parameters.
Structural Model of Populational analysis.
In populational analysis what is epsilon?
The distance from the population to the observed data for an individual patient.
Estimate population mean parameters by treating all data as if it were from the same individual.
Naive Pooled Data
Estimate each individual’s PK and then use individual parameters to estimate the population mean parameters.
Standard Two-Stage Model
This is the gold standard of populational analysis.
Nonlinear Mixed Effects Modeling.
Estimates fixed and random effect populational parameters simulataneously.
Nonlinear Mixed Effects Modeling.
Use prior distribution of parameters in a population of subjects and data from an individual to estimate the individual’s parameters.
Bayesian Estimation.
In _____________, all data points are assumed to arise from a single individual.
Naive Pooled Data
Name the Analysis:
Advantages: Very Simple, Not limited by patients
Disadvantage: Individual’s are lost, no covariate influence, no separation of error soruce.
Naive Pooled Data
What are the steps to the Standard-Two Stage Model.
- Individual Fitting-> Model is identified separately in all subjects obtaining parameter estimates.
- Report Central Tendencies.-> The population mean (theta) and covariance (omega^2) are calculated as the sample mean and covariance.
What are the disadvantages to the standard two-stage analysis?
- Requires Rich Data from every individual.
- Ignores the precision of the individual estimates.
- Overestimates the population variance.
What approach can be used regardless of whether data is rich or sparase?
Nonlinear Mixed Effects Modeling.
In this form of analysis, one stage is needed estimating fixed effects and random effects simultaneously.
Non-Linear Mixed Effects Modeling.
_________ refers to features common to the entire population. (mean PK parameters, Covariate Factors)
Fixed Effects.
________________ refers to populational variability and measurement of uncertainties. (Interindividual, between occasion variability, residual variability)
Random Effects.
What is ETA on a mixed effects modeling graph of log Cp vs time?
The distance between the population mean and individual parameter. This accounts for random effects.
What is epsilon on a mixed effects modeling graph of log Cp vs time?
The distance between the predicted and observed parameter values for an individual.
Measure of the “spread” of the probability density.
- Standard Deviation (omega)
- Variance (omega^2)
When looking at a distribution curve, what does a wider curve suggest?
The wider the curve, the more variability between the subjects in a populational analysis. Ideally we want to account for any potential covariates, to adjust the data appropriately and reduce the overall width of the distribution curve.
Symbol for variance.
Omega^2
What are some potential sources of residual variability?
- Measurement error in parameter or time.
~Assay error
~Investigator or patient non-complicance. - PK/PD model misspecification.
~Model Inappropriate
~Model Incomplete
~Intraindividual variability
~data errors.
Population PK parameters include:
- Mean Parameter Values
- Quantitative Relationships between parameter values and covariates.
- Variability of parameter values across populations of patients.
The one compartment model following an IV bolus dose is an example of which populational model?
Structural Model
The weight, age, genotype of the subjects is associated with which populational model?
Covariate
The between subject, occasion, and residual variability are associated with which populational model?
Statistical.
Which software is used for Nonlinear Mixed Effect Modeling?
NONMEM
