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The Primary Pharmacokinetic Parameters & Compliance Issues



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.


Clinical Scenario:

A 45 year old lady is being treated for a chest infection with a novel oral antibiotic, A063. The antibiotic is generally well absorbed, though with a variable bioavailability, and is eliminated primarily through hepatic metabolism. The reported elimination half-life is about 12 hours. Trough plasma concentrations exceeding 8mg/L is associated with good therapeutic outcomes and low risk of resistance development, whereas concentrations above 16mg/L may be associated with increasing risks of cardiotoxicity.


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.


Consider a situation where the patient has receved a number of other medications that may interact with the pharmacokinetics of A063.  

Go to the right side panel with the sliders. These sliders allow you to test out any effects the drug interactions might have on A063 pharmacokinetics.


a. Move the slider for Rate of Absorption to the left and to the right. Note if there are effects these changes might have on the pharmacokinetic profile. When you have finished, hit the reset button to return you to the original state.


b. 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. Compare the differential effects Rate of Absorption and Bioavailability have on the pharmacokinetics of A063.


c. Now, hit the Reset button to return the default values. Repeat the exercise for Clearance. Record your comments. What are the similarities and differences beween these and the effects of changing bioavailability.


d. Repeat the exercise with the slider for Volume of Distribution. Compare these changes with that of changing Clearance.


e. Review the different effects each parameter has on the pharmacokinetic profile of this drug. What have you learnt?


f. Other than drug interactions, 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: Compliance Graph


This is a simulated profile of an orally administered antibiotic given twice a day. The red lines represent the upper and lower limits of where you would like the concentrations to be. If the concentrations are too low, there will be loss of bacterial kill and a risk of the development of resistance. On the other hand if they are too high there might be increased risk of cardiotoxicity. The dose given appears to be approximately optimal for the patient.


a. In the right column you will see inputs for non-compliance, with respect to timing of dose and the missing of actual dose. Inputs may potentially be 0%, 20%, 40%, 60%, 80%, representing severity of timing non-compliance; and 0-30% representing frequency of missed doses.


b. Change the non-compliance inputs and note how these affect the adequacy of the dosing regiment.


c​. Use the highest level of non-compliance. Go to the dosing console at the top of the right side bar. Alter the  dosage regiment to see how well you can improve on the pharmacokinetics profile.

Think about how non-compliance affects a) therapeutics and b) the conduct of clinical trials. How can you minimize compliance problems?

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