Concepts

Reference
W.R. Ravis, et al: Pharmacokinetics of Phenobarbital in dogs given multiple doses. American J. Veterinary Research, 50(8), 1343 - 1347, 1989.

Significance
Phenobarbital is given chronically to dogs in order to control epileptic seizures. As time passes, induction of hepatic enzymes produces an increase in the clearance of Phenobarbital. Veterinarians should expect that multiple dose rate adjustments will be required in order to maintain relatively constant plasma concentrations of Phenobarbital. Hepatic disease or drug interactions may also reduce the efficiency of elimination of the Phenobarbital.

Exercise (A)

1) Pharmacokinetic variables on the spreadsheet are preset for dogs given Phenobarbital. Simulation #1 represents a dog receiving Phenobarbital for the first time. Simulation #2 represents a dog that had previously received Phenobarbital for 90 days so that his hepatic enzymes have been induced.

2) Both simulations

• Set the "Upper" Concentration (Upper end of effective range) to 40 µg/ml.
• Set the "Lower" Concentration (Lower end of the effective range)to 10 µg/ml.

3) Review the calculated values at the bottom of the worksheet. PLEASE NOTE, the graph may not include enough data (time axis) for the simulation to reach steady-state. (Calculated Cmax and Cave are for steady state).

4) Review the graph of the simulations.

Exercise (B)

1) For simulation #1

• Change Clt to 0.016
• Change Vz to 0.54
• Change F to 0.69
• Simulation #1 and #2 should now be the same.

2) Alter dose for both simulations so that the average plasma concentration (Cave in calculated values) is approximately 20.

3) Alter the clearance (Clt) value of for Simulation #2 by small increments until the CALCULATED maximum plasma concentration (Cmax) is >40.

Questions (A)

1) What dose rate for Phenobarbital would be required to maintain an average plasma concentration of approximately 20 µg/ml in a dog (#2) that has received Phenobarbital for 90 days?

2) What (calculated) pharmacokinetic parameter(s) are changed most dramatically by the change in clearance?

3) Examine the plasma concentration versus time profiles. Which of the two simulations approaches most closely to steady state when 120 hrs have passed? What pharmacokinetic parameter determines the time that steady state is reached? What dosing factor determines whether or not accumulation occurs?

4) Why is the fraction of the phenobarbital dose absorbed (F) lower after phenobarbital is given for 90 days?

1) What percentage change (percent of the 90 day value) in clearance is required to produce a toxic change in Phenobarbital plasma concentrations?

2) What pharmacokinetic parameter(s) change most with this change in clearance?

3) Would you expect the fraction of the phenobarbital dose absorbed (F) to change when hepatic disease causes a reduction in clearance? Which way would it change?