PHAR 4634 - Chapter 2 Page 7

Computer Simulation of Pharmacokinetic Models - Single Dose - One Compartment

This assignment will not be completed in the laboratory. The assignment can be done individually or in groups of up to five.

Objective

The objective of this assignment is to develop a familiarity with the plasma data obtained after single intravenous or oral drug administration. Data consistent with a one or two compartment model will be examined.

General Methods (MacKinetics)

MacKinetics allows the simulation of plasma concentration versus time data for iv bolus, infusion or oral, single or multiple doses with a one compartment linear, two compartment linear, or one compartment saturable pharmacokinetic model. Consequently it can do more than we need for this first set of exercises. You will be using the one or two compartment pharmacokinetic models. The program disk is available from the section Secretary. After you turn the machine on insert the disk and the program should start automatically. Double-clicking on the MacKinetics icon will start the program from the 'desktop'. To start confirm that the model selected is ONE COMPARTMENT LINEAR from the MODEL Menu, choose ENTER DATA from the ACTION menu. For the exercises this week you will be looking at single dose simulations. THEREFORE remember to enter the same value for 'Dose interval (h) as you choose for 'Maximum for Time Axis'. You should also set the values of MSC and MEC as quite high and quite low, respectively, to avoid error messages regarding overdosing or under dosing the patient. FINALLY, note that MacKinetics requests 't_1/2' values not rate constants so you will need to convert all the suggested rate constants into half-lives before entering the value.

1. One Compartment IV Bolus Administration.

To get started I will suggest a sequence of parameter values for the first exercise, however, from then on you will be free to choose appropriate parameter values to complete each assignment.

Enter the following parameter values; 24 hours for the maximum time, 0 for a linear plot, and 20 mg/liter for the maximum concentration. You might then try an apparent volume of distribution of 30 liter (or 0.5 L/kg), dose 600 mg (or 10 mg/kg), and a half-life of 4 hours. If you have the data entered correctly you can press "Y" (Press "N" to revise a value). After about 10 to 12 seconds you should see the completed curve traced on the screen, and the computer will "beep". When you have finished looking at the graph press return and you will be given a choice of entering new parameters, entering new plot (paper) parameters, or returning to the main menu.

a) What shape does the graph have when plotted in a linear fashion? Can you get the same data plotted on a semi-log (new) plot? What shape is this plot?

b) What happens to the curve when you double the apparent volume of distribution? What happens to the curve when you double the half-life?

2. One compartment IV Infusion Administration.

a) What shape does the curve have if you set the infusion duration to a value less than the maximum time scale? What shape is the curve on semi-log graph paper?

b) Set the maximum time scale to 48 hours, use V = 25 liter and half-life = 8 hours. Set the infusion duration to 48 hours and give an infusion rate to achieve a steady state level of 40 mg/L. How long does it take for the concentration to reach 50%, 75% or 87.5% of steady state?

Using the same parameter values develop a regimen to produce a plasma concentration of 20 mg/L six hours after turning off a 2 hour infusion.

3. One Compartment Oral Administration

Enter suitable parameter values and produce a linear and a semi-log graph.

a) Describe the plasma concentration time curve on linear and semi-log graphs.

b) Change the ka values and plot the lines on the one graph. Describe what happens as ka gets smaller. Change ka so that it is smaller than kel. Has the shape of the curve changed? What happens to the time of the peak concentration as you change ka? What do changes to DOSE or V do to the curve?

WRITE-UP

The programs can produce printer output of the plot you have on the screen. You can have more than one line on each graph. You might try to get two or three lines on a graph so that you can illustrate a point with one graph. You can photocopy the printer output for each member of the group however each person should write up their own comments. Briefly describe each graph that you produce, answering the questions as appropriate. Show your calculations for the infusion dosing regimen.

This page was last modified: 12 February 2001