PHAR 4634 - Chapter 22 Page 10    ## Computer Simulation of Pharmacokinetic Models - Multiple Dose

Again, this assignment will not be completed in the laboratory or necessarily during the assigned lab period. It will be due however, approximately one week after your normal lab period. 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 multiple intravenous or oral drug administration. Data consistent with a one or two compartment model will be examined.

General Methods

The general methods will be the same as described for last weeks assignment. Plasma concentration data obtained after drug administration will be simulated using MacKinetics. This program will produce a linear or semi-log plot of plasma concentration versus time data given suitable parameter values.

1. One Compartment IV Bolus Administration - Uniform Dosing Interval - Uniform Dose.

Start with the following parameter values, maximum time = 48 hours; linear plot (0); and maximum concentration = 40 mg/L. Use the parameter values of 30 L for the apparent volume of distribution; 500 mg every 6 hours for the dosing regimen; and a half-life of 4 hours.

a) What shape does the graph have on linear or semi-log graph paper?

b) What happens to the maximum and minimum values if you decrease the half-life, increase the dose, or change the dosing interval?

c) How long does it take to reach 50% of the maximum steady state value? You may have to increase the maximum time scale and give quite a few doses to see this easily. Also decrease the dose and increase the number of doses (in extreme, dose every hour).

2. Two compartment IV Bolus Administration - Uniform Dosing Interval - Uniform Dose.

Enter similar parameters as for "1" above.

a) How does the shape of the plot differ (start with ktp and kpt = 0.5 hr-1)? Use a dosing interval of at least 8 hours.

b) How long does it take to reach 50% of the plateau value? How does this compare with the time it takes with the one compartment model? As with 1c, try increasing the number of doses, shorter dosing intervals.

3. One compartment IV Bolus and Infusion Administration.

Enter suitable plot parameter values.

a) What shape does the curve have with 30 minute infusions given every 4 hours, on linear or semi-log graphs? (NOTE: No iv bolus doses are given for this part).

b) Enter parameter values to produce a plasma concentration of 25 mg/L quickly. [kel = 0.15 hr-1 and V = 12L]. Remember Cp(ss) = k0/(kel*V) = k0/TBC, where TBC = total body clearance. You should try one bolus and one infusion rate and/or two infusions (fast and slow) with no bolus dose.

4. One compartment Multiple Oral Administration.

a) Using parameter values of ka = 1.0 hr-1, V = 20L, and elimination half-life = 4 hr generate the plasma curve for 600 mg doses at 0, 6, 12, 24, 30, and 36 hours. Describe the shape of this curve and the therapeutic implications of this dosing regimen.

b) Vary the elimination half-life value until the above dosing regimen is satisfactory (i.e. more uniform plasma concentrations). Don't forget to change the maintenance dose by the same proportion. Discuss this result briefly.

WRITE-UP

Describe each of the parameter sets that you try. One of the options after the plot has been produced is to print it out on the printer. You can enter a descriptive title and the program will then print the plot on paper. Don't print out every plot you try, only the better ones. Also don't take the plots off the printer until you have finished the whole exercise. That way you will be able to get more graphs on the same amount of paper.

Section 3b. Show your working when calculating the doses that you use.    