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PH3503- Formulations 3 > Lec 6- Oral dose > Flashcards

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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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?
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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
    *
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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
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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
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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
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16
Q

PK of drug absorption- calculate absorption rate constant (ka) and half-life (t1/2a)

A

Absorption rate constant

  • the gradient of this line may be used to calculate the absorption half-life, t1/2a as well as the absorption rate constant ka
  • ka= gradient x 2.303

Absorption half-life

  • The absorption half-life (t1/2a) is related to the absorption rate constant by the following equation
  • t1/2a = Ln2 / ka
17
Q

PK of drug absorption

Method of residuals

A
  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
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

PH3503- Formulations 3 (21 decks)

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