Populational PKPD Analysis

Question 1

The ______ used to measure drug concentrations also has variability.

Answer 1

Assays.

Question 2

Variability is not a major concern for what drugs.

Answer 2

Those that don’t have a narrow therapeutic window.

Question 3

Factors affecting PK/PD are known as ____________

Answer 3

Covariates.

Question 4

This form of PK analysis focuses on:
1. Homogenous Population
2. Single Dose Studies
3. Small Study Groups
4. Intensive Sampling

Answer 4

Traditional PK analysis

Question 5

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.

Answer 5

Routine Clinical Trials.

Question 6

Quantitative relationship between parameter values and co-variates.

Answer 6

Covariate Model of Populational Analysis

Question 7

Variability of parameter values across populations of patients.

Answer 7

Statistical Model of Populational Analysis.

Question 8

Analyzes mean PK parameters.

Answer 8

Structural Model of Populational analysis.

Question 9

In populational analysis what is epsilon?

Answer 9

The distance from the population to the observed data for an individual patient.

Question 10

Estimate population mean parameters by treating all data as if it were from the same individual.

Answer 10

Naive Pooled Data

Question 11

Estimate each individual’s PK and then use individual parameters to estimate the population mean parameters.

Answer 11

Standard Two-Stage Model

Question 12

This is the gold standard of populational analysis.

Answer 12

Nonlinear Mixed Effects Modeling.

Question 13

Estimates fixed and random effect populational parameters simulataneously.

Answer 13

Nonlinear Mixed Effects Modeling.

Question 14

Use prior distribution of parameters in a population of subjects and data from an individual to estimate the individual’s parameters.

Answer 14

Bayesian Estimation.

Question 15

In _____________, all data points are assumed to arise from a single individual.

Answer 15

Naive Pooled Data

Question 16

Name the Analysis:
Advantages: Very Simple, Not limited by patients

Disadvantage: Individual’s are lost, no covariate influence, no separation of error soruce.

Answer 16

Naive Pooled Data

Question 17

What are the steps to the Standard-Two Stage Model.

Answer 17

1. Individual Fitting-> Model is identified separately in all subjects obtaining parameter estimates.
2. Report Central Tendencies.-> The population mean (theta) and covariance (omega^2) are calculated as the sample mean and covariance.

Question 18

What are the disadvantages to the standard two-stage analysis?

Answer 18

1. Requires Rich Data from every individual.
2. Ignores the precision of the individual estimates.
3. Overestimates the population variance.

Question 19

What approach can be used regardless of whether data is rich or sparase?

Answer 19

Nonlinear Mixed Effects Modeling.

Question 20

In this form of analysis, one stage is needed estimating fixed effects and random effects simultaneously.

Answer 20

Non-Linear Mixed Effects Modeling.

Question 21

_________ refers to features common to the entire population. (mean PK parameters, Covariate Factors)

Answer 21

Fixed Effects.

Question 22

________________ refers to populational variability and measurement of uncertainties. (Interindividual, between occasion variability, residual variability)

Answer 22

Random Effects.

Question 23

What is ETA on a mixed effects modeling graph of log Cp vs time?

Answer 23

The distance between the population mean and individual parameter. This accounts for random effects.

Question 24

What is epsilon on a mixed effects modeling graph of log Cp vs time?

Answer 24

The distance between the predicted and observed parameter values for an individual.

Question 25

Measure of the “spread” of the probability density.

Answer 25

1. Standard Deviation (omega)
2. Variance (omega^2)

Question 26

When looking at a distribution curve, what does a wider curve suggest?

Answer 26

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.

Question 27

Symbol for variance.

Answer 27

Omega^2

Question 28

What are some potential sources of residual variability?

Answer 28

1. Measurement error in parameter or time.
   ~Assay error
   ~Investigator or patient non-complicance.
2. PK/PD model misspecification.
   ~Model Inappropriate
   ~Model Incomplete
   ~Intraindividual variability
   ~data errors.

Question 29

Population PK parameters include:

Answer 29

1. Mean Parameter Values
2. Quantitative Relationships between parameter values and covariates.
3. Variability of parameter values across populations of patients.

Question 30

The one compartment model following an IV bolus dose is an example of which populational model?

Answer 30

Structural Model

Question 31

The weight, age, genotype of the subjects is associated with which populational model?

Answer 31

Covariate

Question 32

The between subject, occasion, and residual variability are associated with which populational model?

Answer 32

Statistical.

Question 33

Which software is used for Nonlinear Mixed Effect Modeling?

Answer 33

NONMEM