Concepts
Manipulate drug dose and interval to produce plasma concentration profiles that achieve target Cmax (peak), Cmin (trough) and Cave (average) plasma concentrations.

• Identical rates of drug administration (mg/kg/hr) produce the same average plasma concentration regardless of dose or dose interval.
• For a given dose rate, higher doses (and longer intervals) produce higher peaks (Cmax) and lower troughs (Cmin)

Understand the impact of a change in dose and interval on drug effects in a patient.

• The relative importance of peak, trough or average concentration depends on the pharmacodynamics of the drug. (Critical for gentamicin, less important for phenobarbital and digoxin.)

Significance
Frequently, dose recommendations in the literature are specified as ranges of both dose and interval. (Kirk Current Veterinary Therapy XI lists a dosage for prazosin of 0.5 - 2.0 mg q8 - 12H PO). Although some of this range is necessary to make dosing practical (there are a limited number of tablet sizes available), not all doses and intervals produce the same effect and/or toxicity. It is important to understand the effect of changing dose rate and dose and interval.

Exercise

1) Pharmacokinetic variables on the spreadsheet are preset for a typical adult epileptic dog that has been given Phenobarbital for 90 days.

2) All simulations

• For the purposes of this exercise, ignore the Upper and Lower Target Concentrations. You may set both to 0.

• Change the dose to 3 mg/kg
• Change the dose interval to 6.

• Change the dose to 4 mg/kg
• Change the dose interval to 8

• Change the dose to 6 mg/kg
• Change the dose interval to 12.

• Change the dose to 12 mg/kg
• Change the dose interval to 24.

6) Review the calculated values at the bottom of the worksheet. Pay particular attention to the values for Cmax, Cmin and Cave (and note that Cave is the same for all simulations).

7)Review the graph of the simulations.

Questions

1) Show your calculation of the dose rate for phenobarbital in dogs for simulation #1 and simulation #2. The appropriate equation can be found in the help file under the heading "Dose Interval".

2) Show your calculation of the average plasma concentration for simulation #1 and #2.

3) Because phenobarbital is a sedative, what differences in patient behavior might you expect between simulation #1 and #4?

4)Imagine a smooth curve through the average concentration of all dose intervals (1/2 way between the peak and trough will work for this). The curve shows you what a sustained constant (zero order) intravenous infusion would look like if it were administered at a rate designed to produce the same average steady-state concentration.

Calculate the intravenous infusion rate based on the Cave produced in all of the oral simulations. Please pay special attention to the difference between the equation for Cave for intravenous administration and Cave for non-intravenous routes (F is part of the average concentration calculation for non-intravenous routes but it is not included in the equation for the intravenous route - be sure you understand why.)