The Volume of Distribution, Clearance & Compliance on the Pharmacokinetics Profile
1. To appreciate how the primary pharmacokinetic parameters of 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.
2. To appreciate how interindividual variability in PK and response may arise.
3. To appreciate how non-compliance may make therapeutics more difficult.
Useful videos to watch:
Introduction to Pharmacology playlist
Dr Chandra is prescribing a newly developed analgesic drug, NP0086, for a 63 year old lady. NP0086 has been recommended to be administered 150 mg twice a day. NP0086 is well absorbed when administered orally, and is eliminated by hepatic metabolism (80%) and renal excretion (20%). Clinical studies have established that the minimal effective concentration is approximately 10mg/L. Concentrations above 20mg/L are associated with marked sedation and respiratory depression.
1. Let’s begin by going to the following interactive graph at https://www.pharmacologytutorials.com/halflife
You should see this page
a) This graph was obtained following an IV dose of 150mg. Are you able to estimate the Volume of Distribution of NP0086 in this patient?
b) What is the elimination half-life for NP0086 in this lady?
c) On the right, you will see 2 slider bars. The top slider is for Clearance. You can modify the Clearance for NP0086 by sliding to right or left. You can move the slider completely to the right, and then completely to the left. What can you say about how changing the Clearance affects the pharmacokinetics profile of NP0086.
d) Reset the graph by hitting the Reset button at the top of the right column. Now move the slider bar for Volume of Distribution all the way to the right, and then to the left. How do the effects differ from what you had previously observed using the Clearance slider? Explain.
e) Hit the reset button. Now move both slider bars all the way to the right, and then all the way to the left. What do you observe? Explain what you observe.
2. Now, go to this page:
This is what a multiple dose 12 hourly regimen looks like for NP0086. Here you find the concentrations are exactly where you would like it to be – between 10mg/L and 20 mg/L.
a) Move the slider for Clearance once again, to the left, then to the right. What do you notice about the steady state concentrations? What is the time taken to reach steady state? Can you estimate the effect changing the Clearance has on the ‘Fluctuations’, and the ‘Accumulation’ of NP0086?
b) How do these help you in understanding therapeutics?
c) Reset the graph. Now repeat the exercise by using the Volume of Distribution slider. How are the changes different from what you had observed previously with changing Clearance?
d) What is the impact of these changes (Clearance and Vd) on the efficacy and toxicity of NP0086 at the recommended dose?
e) What are common causes of changes to Clearance? What are the common causes of changes to Volume of Distribution?
3. Now go to this page
You should see this page that allows you to create a dosing regimen.
In the middle of the right column you will see the dosing module.
Notice the half-life is about 12 hours.
Enter the minimum and maximum for the therapeutic range. They should be 10 and 20 respectively.
Next, enter the tablet size of 75.
For the actual dosing regimen, enter No of Doses - 10, Dosing Interval as 12. These should create a dosing regimen of 10 doses of 2 tablets (150mg) given every 12 hours.
When you are ready, click the “Add to the Below Table” button.
This should generate a plasma concentration profile for 10 doses, somewhat similar to the one that you saw in the previous exercise.
a) Now, click the Randomize button, . This will generate a random patient different from the previous idealized patient. Notice if there are differences in pain relief or risk of toxicity.
b) Click the Randomize button 10 times. Notice how every patient will have a different drug response.
4. Finally, go to this page:
This page allows you to check the effect of non-compliance on the pharmacokinetics profile.
In the right column, you will find settings for non-compliance – for Timing and Dose. The first affects the non-compliance with respect to the timing of each dose. The second affects the variability with respect to missing a dose. Vary these settings from the lowest to the highest non-compliance.
a) How does non-compliance affect the analgesic efficacy and risk of toxicity?
b) What increases the likelihood of non-compliance? Think of ways to mitigate these problems.