Clinical Pk

Question 1

what is responsible for the variability in response to drugs between patients

Answer 1

different Cp (plasma concentration of drug)

Question 2

the variability in drug plasma concentration of drugs is especially important for drugs with (3 words) because____

Answer 2

• narrow therapeutic index
• the dose that is effective is very close to the dose at which toxic effects occur, i.e. ratio of the minimum toxic plasma level to the minimum effective dose is very small
  
  • little room for error

Question 3

how are drugs with narrow therapeutic index managed medically

Answer 3

through drug plasma level monitoring

Question 4

name 4 classes of drugs for which plasma level monitoring is common, provide examples for each class

Answer 4

• Antiarrhythmic Drugs
  
  • e.g. Procainamide
• Antibiotics
  
  • Vancomycin
• Anticonvulsants
  
  • phenytoin
• Psychotropics
  
  • lithium

Question 5

what are the 2 key parameters that need to be known to determine the mean steady state plasma level (Cpss)

Answer 5

• volume of distribution (V)
• elimination rate constant (K)

Question 6

what is this equation and what do each of the variables stand for

Cpss = FD/tau x Cl = FD/(tau x K x V) = FD t_1/2/ (tau x 0.693 x V) where

Answer 6

• Drug plasma concentration at steady state
• F = bioavailability
• D = dose of drug administerd
• tau = dosage interval
• Cl = clearance
• V = volume of distribution
• K = loss rate constant

Question 7

Dose adjustment may be warranted when the following physiological factors exist (3)

Answer 7

• weight issues
• chronic heart failure
• renal or liver issues

Question 8

renal function is assessed or measured by

Answer 8

creatinine clearance (Clcr)

Question 9

creatinine is eliminated almost exclusively by

Answer 9

glomerular filtraton

Question 10

what will impairment of glomerular filtration result in

Answer 10

• decrease in excretion rate of creatinine,
  
  • i.e. decrease in Clcr, and serum creatinine concentration rises

Question 11

although creatinine clearance can be calculated, this biomarker is most often used to measure renal function

Answer 11

serum creatinine

Question 12

Serum creatinine is inversely related or directly proportional to glomerular function?

Describe the equation

Answer 12

• inversely related
• Clcr = k₀/SCC where
  
  • SCC = serum creatinine
  • ko is the constant rate of production of creatinine in the body

Question 13

as it relates to the equation below, when renal or kidney function decline, serum creatinine decreases or increases

Clcr = Ko/Scc

where Scc = serum creatining

Ko = rate constant - production of creatinine in the body

Answer 13

decreases because serum creatinine levels are inversely proportional to glomerular filtration

Question 14

these tools used by physicians (what are these?) relate creatinine clearance to serum creatinine, gender, body weight and height are are used to

Answer 14

• nomograms
• calculate the dose for the patient based upon the estimate of creatinine clearance from serum creatinine levels

Question 15

biomarkers for metabolic (liver) function are readily available (true/false)

Answer 15

false

Question 16

when liver function is reduced, drug metabolism is severly or mildly impacted

Answer 16

mildly

Question 17

when studies are conducted in normal healthy volunteers, what are the issues with dosing and dosing regimen as it relates to use in real life. Why?

Answer 17

• the study doesn’t mimic the pt population that will use the drug i.e. healthy volunteers compared with disease state patients
• limited ethnicities or underrepresentation of gender
• comorbid conditions and con-meds excluded
• well controlled parameters for trials

Question 18

Population pharmacokinetics looks at

Answer 18

ways to obtain more representative estimates of pK parameters in different pt populations

Question 19

what are the three clinical study phases, what do they typically assess

Answer 19

• Phase I studies
  
  • small study 12-100 subjects
  • healthy volunteers, intensive sampling, calculate mean values
  • safety study
  • sub therapeutic dose but with dose ranging/ascending dose
• Phase II
  
  • 100 - 300 subjets
  • disease state
  • safety and efficacy at therapeutic dose
• Phase III
  
  • large study
  • disease state, less sampling
  • efficacy, effectiveness, safety
  • estimate population parameters

Question 20

What are 3 statistical approaches to estimation of pK parameters

Answer 20

• Conventional
  
  • non-compartmental analysis
  • model fitting by non-linear regression
• Multiple regression analysis
• non-linear mixed effect modelling

Question 21

the conventional approach to estimation of pK parameters determines population parameters by

Answer 21

• intermediate estimation of parameters in each member of a group of individuals

Question 22

what are common pk parameters measured or analyzed via the conventional approach

Answer 22

• mean and std deviation for each parameter
  
  • e.g. gender, ethnic group, responders/non-responders
• Clearance (Cl); Volume of distribution (Vd); Plasma concentration (Cp)

Question 23

how are pk parameters estimated in the conventional approach (2 statistical methods)

Answer 23

• non-compartmental analysis
• model fitting using non-linear least squares regression analysis

Question 24

this statistical method does not require a specific model​

Answer 24

non-compartmental analysis

Question 25

what pK parameters is noncomparmental analysis based upon (4)

Answer 25

1. AUC 2. Cp vs time 3. slope 4. terminal beta phase

Question 26

what 4 pK parameters are calculated in noncompartmental analysis

Answer 26

1. AUC 2. Vd 3. Cl 4. halflife

Question 27

True/False: Model fitting fits the selected pK model to pk response data (Cp and t) and attempts to provide parameter estimates that minimize differences between observed and predicted values

Answer 27

True

Question 28

Error or variability in model fitting is a result of (3)

Answer 28

* random error relating to **independent variable**s (time) e.g. errors in recording of drug administration time * random errors related to **dependent variables** (Cp) e.g. assay measurement * intraindividual variation

Question 29

to account for errors and avoid bias the model is linked to a \_\_\_\_\_\_\_\_\_\_\_\_model

Answer 29

variance

Question 30

Nonlinear least squares regression analysis is an iterative process that modifies parameters until criterial for good fit are met. This is done by fitting non linear data to

Answer 30

* differential and integrated equations (NonLin) * extended least squares method (Elsfit)

Question 31

Multiple regression analysis using SAS or SPSS do this

Answer 31

determines the impact of demographic, phsiological and pathological factors on pK

Question 32

SPSS multiple regression analysis assesses

Answer 32

* the relationship b/t pk parameters (Vd, Cl) and predictors (age, sex etc) * calculates contribution of each predictor to the pK parameter * tests signficance

Question 33

SAS allows development of

Answer 33

* predictive models for pk parameters * considers all regressions and generates model with highest R² * uses predicted sum of squares for model selection * max adjusted R² models compared with othe models * model with minimum predicted sum of squares with fewest independent variables chosen

Question 34

the model that fits a pk model to all data obtained from pooled pts and includes randomly treated errors as well as unusual errors in analysis is called: what is another name by which it is known as

Answer 34

* Non-linear fixed effects modeling (NonMem) * First order method

Question 35

what is an advantage and disadvantage of the first order method

Answer 35

* advantage - do not need a lot of pk data * disadvantage - need large number of subjects

Question 36

what are common sources of error that cause biased estimates in population pK parameters

Answer 36

* Fixed Effects * pt characteristics (age, weight, height, gender) * underlying pathology (comorbid conditions) * concomitant therapy, alcohol intake, smoking * Random Effects * amount of pK variability * interindividual variation (n) * intraindividual variation (assay error)

Question 37

NonMEM analyzes poole data and deals with the concomitant effects on parameter estimation through determination of (3)

Answer 37

* mean values of pk parameters * quantiative relationship to subjects * variability across population