Pharmacokinetics 1 + 2

Question 1

what is pharmacokinetics (PK)?

Answer 1

what the body does to the drug (ADME)

Question 2

what is pharmacodynamics?

Answer 2

what the drug does to the body i.e. mechanism of action

Question 3

what are the stages to collecting and analysing PK data?

Answer 3

1. drug is administered
2. Blood sample is taken
3. Analyse the blood via HPLC or LC-MS or Atomic absorption spectrometry

Question 4

what are the main types of pharmacokinetic (PK) data analysis?

Answer 4

• Non-compartmental analysis
• Compartmental
• Population PK models
• Physiologically-based (PBPK) (bottom-up approach)

Question 5

what is the straight line equation of PK drug elimination?

Answer 5

C = -k.t + Co
C = Conc
K = rate constant
t = time
Co = conc at time zero

(negative sign showing the loss of the drug with time (so a negative line gradient)

Question 6

what is zero order process of drug elimination?

Answer 6

elimination of a constant amount of drug per unit of time, independent of drug concentration

Question 7

what is first order process of drug elimination?

Answer 7

constant proportion of drug eliminated in a defined time period

Question 8

what is absorption?

Answer 8

the transfer of an exogenous compound (i.e. drug) from site of
administration into the systemic circulation

Question 9

what type of compounds cross cell membranes easier and are rapidly absorbed?

Answer 9

lipid-soluble compounds

Question 10

what parameters are looked at when talking about absorption?

Answer 10

Cmax and Tmax

Question 11

what is the trapecoid rule to calculate area under the curve?

Answer 11

the sum of the area of all the trapezoids using this equation: (C1+C2)/2 X (t2-t1) to work out the area of one trapezoid

Question 12

what is bioavailability a measure of?

Answer 12

the extent of absorption after extravascular administration

Question 13

how do we calculate bioavailability?

Answer 13

(% of parent drug in urine after oral dosing) / (% of parent drug in urine after IV dosing)

Question 14

what determines the distribution of drugs into tissues from the blood circulation?

Answer 14

– Its ability to cross cell membranes (based on physiochemical properties)
– Blood flow to individual tissues
– Extent of its plasma protein binding

Question 15

what effect does drug binding to plasma proteins have?

Answer 15

it increased the volume of distribution as if it’s bound to proteins it won’t be able to diffuse into tissues

Question 16

how do we calculate volume of distribution?

Answer 16

(total amount of drug in body) / (conc of drug in blood)

Question 17

what does a volume of distribution of <3L mean?

Answer 17

drug is mostly in plasma

Question 18

what does a volume of distribution of ~40L mean?

Answer 18

even distribution of the drug throughout the body

Question 19

how do we calculate half-life?

Answer 19

t1/2 = 0.693/K

where K= Clearance / vol od distribution

Question 20

how many half-lives does it take usually for a compound to reach steady state?

Answer 20

5 half-lives

Question 21

what are the features of a compartmental fit/model?

Answer 21

• use exponential equations to describe the curve
• accomplished by theoretical compartments and transfer rates
• Can be used for simulations (to an extent)

Question 22

what is the one compartment model?

Answer 22

• assume it’s a linear process

- all tissues and organs are lumped into one compartment

Question 23

what is the two-compartment model?

Answer 23

• assumes the body doesn’t conform to one compartment
• represent a group of similar tissues or fluids
• more flexibility

Question 24

what is the ‘central’ or ‘peripheral’ compartment?

Answer 24

-a compartment including blood, heart, lungs, liver and kidneys

Question 25

what are the features of population pharmacokinetic models?

Answer 25

• intensive and sparse sampling
• computationally intensive
• longer analysis time
• allows provision for PK/PD modeling

Question 26

what are advantages of individual PK analysis methods?

Answer 26

1. simple
2. robust
3. model-independent
4. user-friendly
5. rapid

Question 27

what are disadvantages of individual PK analysis methods?

Answer 27

1. assumes linear PK
2. Single analysis - cannot address multiple doses
3. study design often limits analysis
4. model - independet

Question 28

what are advantages of population PK analysis methods?

Answer 28

1. robust
2. provides structural model for PK/PD
3. Any route of admin
4. Linear and non-linear PK supported
5. descriptive and predictive
6. studies can be pooled

Question 29

what are disadvantages of population PK analysis methods?

Answer 29

1. less rapid
2. less user-friendly software
3. more expertise required for analysis

Question 30

What is PBPK and how is it different from ‘traditional’

PK approaches?

Answer 30

• traditional PK approaches lump kinetically similar tissues together in a way that typically bears no relation to anatomical structure or physiology
• PBPK has compartments representing organs or tissues whose drug conc are assumed to be uniform

Question 31

what can we use the PBPK model approach for?

Answer 31

• simulation of clinical trials without the need for clinical data
• estimation of tissue specific drug concentration
• assessment of potential for drug-drug interactions

Question 32

what effect does a change in dose have on non-linear pharmacokinetics?

Answer 32

• causes a disproportionate change in AUC

- affects metabolism, transport(distribution) and absorption

Question 33

true or false:
‘the rate of elimination is not proportional to the concentration or
to dose given’?

Answer 33

True

Question 34

what is the role of pharmacokinetics in drug development?

Answer 34

to look at:
• In vivo (animal models)
• In man (phase I clinical trial – first in man)
• In clinic (several stages of clinical trial before
drug approval)

Question 35

why can small animals tolerate relatively larger doses?

Answer 35

as they have a more rapid clearance rate.

Question 36

what factors are considered when you individualise a dose?

Answer 36

– Renal function
– Hepatic function
– Genetics

Question 37

what is used to help predict drug action/metabolism?

Answer 37

– Liver function tests
– Marker compounds
– Pharmacogenetics

Question 38

what are you testing for in liver function tests?

Answer 38

-bilirubin levels
-liver function enzymes
(if these are raised, shows a sign of hepatic dysfunction)

Question 39

what is Pharmacogenetics?

Answer 39

Study of how genetic variations affect drug response

Question 40

in therapeutic drug monitoring, what is monitored in the clinical trials?

Answer 40

efficacy and toxicity

Question 41

in therapeutic drug monitoring, what is monitored in the lab tests?

Answer 41

pharmacokinetics, pharmacodynamics and pharmacogenetics

Question 42

what are the characteristics of drugs with a potential for therapeutic dose monitoring?

Answer 42

(i) variable or unpredictable relationship between dose and resulting plasma
drug concentrations
(ii) narrow therapeutic window
(iii) ability to correlate measured drug concentration with efficacy and/or
toxicity
(iv) availability of reliable and clinically feasible assays

Question 43

what is ‘therapeutic window’?

Answer 43

- range of drug exposures that
produce a therapeutic response
without causing any significant
adverse effect in patients
(the range
between minimum effective
concentration and minimum
toxic concentration)