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TUTORIAL 1

The Primary Pharmacokinetic Parameters

 

Objectives:

To appreciate how the primary pharmacokinetic parameters of bioavailability, absorption rate, volume of distribution and clearance affect the shape of the pharmacokinetic profile of a multiple dose regimen at steady state, with a focus on half-life, time to reach steady-state, steady state concentration, peak-trough fluctuations and accumulation.

 

Useful videos to watch:
The Pharmacokinetics series: Determinants of Elimination Half-life
The Pharmacokinetics series: The Elimination Half-life
Understanding the Common Dosing Schedules
Understanding Therapeutics

 

 

Let us start with this interactive graph. Open this in a new tab.

Effect of the primary pharmacokinetic parameters on half-life.

You will see this graph with a PK plot of drug concentrations following a multiple oral dose regimen. On the right hand side, you will see a panel with interactive sliders for the 4 primary pharmacokinetic parameters – Bioavailability, Rate of Absorption, Clearance and Volume of Distribution. At the bottom you will see the half-life value of 12 hours.

 

So the drug in this simulated patient, with the default pharmacokinetic parameters, has a half-life of 12 hours.

 

Exercise 1.

 

a. What is the dosage interval here?

 

b. Note where the steady-state for this dosage regimen begins.

 

c. Place your cursor over the peak of the particular dose when the concentrations first begin to achieve steady-state. A pop-up box will appear with the time and concentration at the position. Record the time and concentration. Do the same for the trough concentration that follows.

 

An average of those concentrations will represent the average concentrations at steady state.

 

Dividing the Peak by the Trough will give you a measure of the concentration fluctuations that occur during steady-state for a multiple dose regimen, such as the one you have administered..

 

e. Now, make a similar record of the Peak and Trough concentrations following the initial dose. Dividing the steady state average concentration by the first dose average, will give you a measure of the accumulation that has occurred between the first dose and steady-state.

 

Well done! You have completed your first exercise. You now have measures for half-life, time to reach steady-state, average, peak and trough concentrations at steady-state, fluctuation and accumulation. These are all the measures you need to understand the pharmacokinetic behaviour of the drug.

 

 

Exercise 2.

 

a. Go to the right side panel with the sliders.

 

Move the slider for Bioavailability to the left and then to the right. This effectively alters the Bioavailability in this simulated patient. Explore the effect Bioavailability has on the parameters you have measured in the previous exercise. Make a note of you findings.

 

b. Now, hit the Reset button to return the default values. Repeat the exercise for each of the other parameters. Record your comments.

 

c. Review the different effects each parameter has on the pharmacokinetic profile of this drug.

 

d. Consider what may cause these parameters to vary.

 

e. Consider the effect these changes have on the therapeutic effects of the drug.

 

 

Exercise 3.

 

Open this site in a new tab so you do not lose your previously opened pages.

Pharmacokinetics Vizualizer – Multiple oral dose antibiotic

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This is a simulated profile of an orally administered antibiotic given 250mg twice a day. The grey zone represents the concentrations you would like to produce. If the concentrations are too low, there will be loss of efficacy. On the other hand if they are too high there might be increased risk of cardiotoxicity.

 

a. Click the green button that says Population View. This randomly generates 20 patients given the same dose. The red line represents the population average.

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b. Now click the blue button that says Change Population. Each time you click this button, a fresh selection of 20 patients are simulated. Do this 10 times. Effectively this will allow you to view a total of 20 x 10 = 200 patients.

 

c. Make a note of the extent of variability in the 200 patients.

 

d. Comment on the impact this variability has on the efficacy and safety of this antibiotic.

 

e. On the right side panel, there is a box that allows you to redesign the dosage regimen. Explore how the concentration profile changes with changes in the dosage regimen.

 

f. Can you design a dosage regimen that is good for everyone in the population?

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