Lec 6- Oral dose Flashcards
1
Q
PK of drug absorption- using the equations
A
- 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
2
Q
Drug absorption rate constant (Ka)- Changes in the abosrption rate
A
- 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
3
Q
Drug absorption
Absorption rate constant (Ka)
A
- 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
4
Q
The extent of drug absorption- Bioavailability (F)
What is bioavailability a measure of
A
- 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
5
Q
Drug absorption- Bioavailability (F)
Why is bioavailability important
A
- 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
6
Q
Drug absorption- Bioavailability (F)
Bioavailability is also important for generics
A
- 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
7
Q
Drug absorption- Bioavailability (F)
Changes in the extent of absorption
A
- 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
8
Q
PK of drug absorption- Body weight
A
- 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
9
Q
PK of drug absorption- Body weight
Doubling dose
A
- 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
10
Q
PK of drug absorption- formulations
What is the difference between the two profiles
A
- 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
11
Q
PK of drug absorption- disease state
From red to black
A
- 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?
12
Q
PK of drug absorption- Volume of distribution
ACEI
A
- 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
*
13
Q
PK of drug absorption- Volume of distribution
Other options
A
- 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
14
Q
PK of drug absorption- ka and Kel
Elimination rate constant
A
- 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
15
Q
PK of drug absorption- ka and Kel
Absorption rate constant
A
- 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 t1/2
18
Q
PK of drug absorption- method of residuals
A
- 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
19
Q
PK of drug absorption
A
-
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
