Lec 6- Oral dose

Question 1

PK of drug absorption- using the equations

Answer 1

• Understanding the concept of oral drug absorption is important as this will be the most commonly used approach to deliver drugs to patients that you will encounter
• Absorption is into the portal circulation
• NOT into the body, the latter being bioavailability
• Most important factors- the rate of absorption, extent of absorption

Question 2

Drug absorption rate constant (Ka)- Changes in the abosrption rate

Answer 2

• Impacts on the time required to elicit a clinical response and hence the onset
• The rate affects the peak (Cmax) and the time it takes to reach the peak (tmax)
• Drug: poorly absorbed
• Formulation: Excipients or release type
• Food effects

Question 3

Drug absorption

Absorption rate constant (Ka)

Answer 3

• Changes in the rate of absorption
  
  • Impacts on the time required to elicit a clinical response and hence the onset
  • The rate affects the peak (Cmax) and the time it takes to reach the peak (Tmax)
• Drug poorly absorbed
• Formulation: excipient or release type
• Food effects

Question 4

The extent of drug absorption- Bioavailability (F)

What is bioavailability a measure of

Answer 4

• Fraction of the dose administered that reaches the systemic circulation
• Its a number between 0-1 (0-100%)
• The term given is F
• For different doses you need to correct for the dose
• NB it has now flipped
• Fo = oral bioavailabiltiy

Question 5

Drug absorption- Bioavailability (F)

Why is bioavailability important

Answer 5

• What was shown on the previous page is an example of what is termed the absolute bioavailability of a drug
  
  • It is a useful marker for understanding how effective a drug is at reaching the circualtion following a dose
• If oral F is low (e.g. <30%) it means we require careful consideration of how our product is formulated

Question 6

Drug absorption- Bioavailability (F)

Bioavailability is also important for generics

Answer 6

• In this case we refer to the ‘relative bioavailability’ where we compare a test (generic) against a reference (innovator) product
• We want to show our product is comparable to the brand leader to ensure it can gain MA

Question 7

Drug absorption- Bioavailability (F)

Changes in the extent of absorption

Answer 7

• If the TW is between 0.25-0.5mg/mL, the ‘black’ drug shows poor (F) and doesn’t even reach the Therapeutic Window (TF) to elicit a clinical effect
• The red drug shows sufficient bioavailability to give a good clinical response
• Same drug BUT different formulation
• Metabolism problems; Formulation problems- may need to check the rate of absorption

Question 8

PK of drug absorption- Body weight

Answer 8

• Giving an oral dose of a drug to two different patient
• Same dose to underweight (red) and Overweight patient
• Higher dose for overweight
• What is different between the 2 patients?
  
  • Distribution- Vd

Question 9

PK of drug absorption- Body weight

Doubling dose

Answer 9

• Providing there is no change in the half-life or bioavailability if we give double the dose in the same patients, the Cmax will also double proportionally but the time to Cmax won’t change
  
  • This is due to the absorption rate

Question 10

PK of drug absorption- formulations

What is the difference between the two profiles

Answer 10

• What is the difference
  
  • Absorption
• Any changes in elimination
  
  • No
• What are the possible reasons for any changes
  
  • Liver
  • Drug-drug interactions
  • Change in formulation

Question 11

PK of drug absorption- disease state

From red to black

Answer 11

• The absorption rate hasn’t changed as we are doing the same drug in the same patient
  
  • The results show a slight change in the Cmax and tmax
• Clearly, the elimination part has altered and appears to be an increase- the black profile shows faster elimination than the red profile
  
  • This is confirmed in the reduction in half-life and change in the AUC
• This example is an example where the clearance has increased by 50%
  
  • This could be a result of a drug-drug interaction
• Carbamazepine which induces the metabolism of co-administered drugs = enhanced metabolism = enhanced clearance = poor clinical effect of the original drug
• How would you overcome this?

Question 12

PK of drug absorption- Volume of distribution

ACEI

Answer 12

• What is the Vd for this drug
• Conc = dose / volume
• You cannot take the intercept of the graph to work out C₀ and then Vd
• Why do you think that is
  *

Question 13

PK of drug absorption- Volume of distribution

Other options

Answer 13

• When trying to calculate the volume of distribution for an orally dosed drug, we often have to focus on other relationships between pharmacokinetic terms
• Assuming the following data: DOSE= 100mg; AUC = 1435ng/mL.h
• You can then surrogate approaches to calculate the volume of distribution for this drug

Question 14

PK of drug absorption- ka and Kel

Elimination rate constant

Answer 14

• Providing you have log-transformed your data (Log₁₀ or Ln) you can calculate the elimination rate constant or half-life from the terminal phase of the graph as you do for the IV-bolus and IV-infusion scenarios

Question 15

PK of drug absorption- ka and Kel

Absorption rate constant

Answer 15

• You use the method of residuals, but extrapolating the terminal phase best fit line, to calculate residuals (differences) between absorption phase points and corresponding best-fit line points and then plotting these out
• Use the same linear equation approach to calculation ka and even t_1/2

Question 16

PK of drug absorption- calculate absorption rate constant (ka) and half-life (t_1/2a)

Answer 16

Absorption rate constant

• the gradient of this line may be used to calculate the absorption half-life, t_1/2a as well as the absorption rate constant ka
• ka= gradient x 2.303

Absorption half-life

• The absorption half-life (t_1/2a) is related to the absorption rate constant by the following equation
• t_1/2a = Ln2 / ka

Question 17

PK of drug absorption

Method of residuals

Answer 17

1. Table of data
2. Use log scales (semi-log paper OR normal paper with Ln)
3. Draw data points on graph (gives a curve)
4. Not good, we need a straight line
5. Aim to draw as straight lines (for both absorption and elimination)
6. Separate absorption from elimination
7. Calculate the absorption rates

Question 18

PK of drug absorption- method of residuals

Answer 18

• Extrapolate line to get data points
  
  • Extrapolate up to get these data on the line for each of the time points- Go up, Go left, New concentration
• New concentration- Original points= final points to plot
  
  • Plotting the residuals on the graph will give another straight line
  • This line can be used to calculate the gradient which gives the absorption rate constant

Question 19

PK of drug absorption

Answer 19

• Absorption rate constant
  
  • The gradient of this line may be used to calculate ethe absorption half lifet1/2 as well as the absorption rate constant Ka
• Absorption half-life
  
  • The absorption half-life t1/2 is related to the absorption rate constant by the following equation